Bioerodible implant for long-term drug delivery and associated methods of manufacture and use

ABSTRACT

A drug delivery system is provided in the form of a controlled release, bioerodible pellet for subdermal implantation. The pellet is bioerodible, and provides for the sustained release of a pharmacologically active agent over an extended time period. As such, the drug delivery system finds significant utility in chronic drug administration. Bioerosion products are water soluble, bioresorbed, or both, obviating the need for surgical removal of the implant. Methods for manufacturing and using the drug delivery system are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e)(1) toprovisional U.S. Patent Application Ser. No. 62/401,167, filed Sep. 29,2016, the disclosure of which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

(1) Technical Field:

The invention relates generally to controlled release drug deliverysystems, and more particularly relates to bioerodible implants forcontrolled release of a pharmacologically active agent over an extendedtime period. The invention finds utility in the fields of drug delivery,pharmaceuticals, medicine, and public health.

(2) Description of Related Art:

Many individuals must take medication on a regular basis for asignificant period of time. Such chronic pharmacotherapy is necessaryfor many different types of drugs prescribed in a wide variety ofcontexts, ranging from antidepressant and antipsychotic medicationstaken several times a day to prevent a serious mental health setback, toantiretroviral “cocktails” that require an ongoing and complicateddosage regimen to effectively treat a potentially fatal disease such asAcquired Immune Deficiency Syndrome (“AIDS”). A lack of patientcompliance in such cases, including even a relatively small divergencefrom a prescribed dosage regimen, can adversely affect a patient'shealth and well being and even jeopardize a patient's life.

Furthermore, there are numerous medications that can diminish a person'sability to think clearly or adversely affect short term memory, in turnimpacting on a patient's ability to follow a prescribed dosage regimen.It is well known, for example, that many life-saving cancer drugs areassociated with so-called “Chemotherapy-Related Cognitive Impairments,”sometimes referred to as “chemo brain” or “chemo fog,” which reduces thelikelihood that the cancer patient can adhere to a required dosageregimen.

A reliable drug delivery system for chronic administration of one ormore pharmacologically active agents could overcome the problems notedabove, eliminating the need for rigorous compliance with a prescribeddrug dosage regimen.

Such a system would also be useful in the long-term, controlled releasedelivery of active agents that are commonly administered orally, as adelivery system for continuously administering a drug over a period ofmonths, or even years, would not involve oral administration. Superiorlong-term drug delivery systems would thus be useful with drugs thatexhibit low oral bioavailability as a result of first-pass metabolism orincomplete absorption. Drugs that exhibit a significant first passeffect include well known and often prescribed drugs such as imipramine,propranolol, buprenorphine, diazepam, cimetidine, and nitroglycerine,among others.

An effective long-term controlled release delivery system would also beuseful to administer drugs that are usually given orally, but where oraladministration often results in moderate to severe gastrointestinal(“GI”) side effects. For example, oral administration of nonsteroidalanti-inflammatory agents (commonly known as “NSAIDs”) is associated withnumerous GI side effects that include nausea and vomiting, dyspepsia,gastric ulceration, gastric bleeding, and diarrhea. With NSAIDS, theseGI side effects are due to the acidity of the drugs and to theirinhibition of COX-1 and/or COX-2, a mechanism of action that reduces theamount of protective prostaglandins synthesized in the GI tract.Anti-epileptic drugs, pain drugs, and numerous other drugs that arecommonly administered via the oral route are also known to result in amultitude of gastrointestinal side effects.

The idea of using implantable pellets to provide for controlled releaseof an active agent over an extended time period is known. In the area ofcontraception, for instance, drug delivery implants have been proposedas systems that would eliminate the need for daily dosing (as isrequired with oral contraceptive agents) and provide reliablecontraceptive protection for an extended time period, e.g., a year, twoyears, three years, or even longer. An ideal long-term contraceptiveagent would also be “forgettable” insofar as its effectiveness would notdepend on user compliance each day or at each coital act; removablebefore complete absorption, for women who decide to terminate use ofbirth control; and biodegradable, so that removal is not required.

Most of the work on contraceptive implants to date has involved the useof aliphatic polyesters, including polylactic acid (PLA), polyglycolicacid (PGA), polycaprolactone (PCL) and the copolymer of PLA and PGA,poly (lactic-co-glycolic acid) (PLGA); see Pitt et al. (1981) NIDA Res.Monogr. 28:232-53. Such materials have been viewed as attractivecandidates because their degradation products are naturally occurringmetabolites, i.e., lactic and glycolic acid. A polycaprolactone-basedcontraceptive implant, Capronor™, was developed in the 1980s to releaselevonorgestrel for a period in the range of 12 to 18 months and thendegrade. The product was ultimately abandoned, however, because of skinirritation experienced by study participants, stability problems duringstorage, and a long release tail, explained infra.

More recently, long-term controlled release implants have been developedfor the administration of etonogestrel (Implanon®, as well as the newerradio-opaque version, Nexplanon®, from Merck & Co.). See Maddox et al.(2008) P&T 33(6):337-347, the prescribing information for Implanon andNexplanon, and U.S. Pat. Nos. 4,957,119, 8,722,037 and 8,888,745. Likemany other implants, however, Implanon and Nexplanon must be surgicallyremoved once the active agent is depleted. The need for surgical removalof an implant is inconvenient and potentially risky; issues can arisewith the formation of fibrous tissue around the implant, the failure tolocate implants that may have been inserted too deeply, pain, tissuedamage, local infection, and nerve damage.

In addition, many controlled release implants are associated with a long“tail period” after much of the active agent has been released, in whichthe implant is still releasing active agent but at a sub-effectivelevel; see, e.g., Raymond et al. (1996) Fertil. Steril. 66(6):954-61. Inthe aforementioned study, involving a biodegradable implant, the dosageof the contraceptive agent fell below the minimum effective level forsome time, in some cases for as long as 18 months. This is anunacceptably long time period during which contraceptive agent is stillbeing delivered but at a dosage that is too low to provide acontraceptive effect. Other implants that are bioerodible have alsoresulted in significant tail period.

There is, accordingly, an ongoing need in the art for an implantabledrug delivery system that provides for controlled release of an activeagent throughout an extended drug delivery time period. An idealcontrolled release implant would be (1) bioerodible, thereby obviatingthe need for surgical removal, (2) composed of non-toxic, naturallyoccurring materials, (3) simple, inexpensive, and straightforward tomanufacture, without need for many steps, complicated equipment, toxicreagents, or a great deal of time, and (4) physically and chemicallystable during storage, handling, sterilization, handling, and a possibleearly removal procedure. In addition, an ideal drug delivery implantwould provide for controlled release of an active agent at an effectivelevel over an extended time period, as is necessary with chronicpharmacotherapy. The ideal implant would also have a reduced tail periodrelative to those observed with earlier implants.

BRIEF SUMMARY OF THE INVENTION

Accordingly, the invention is directed to the aforementioned need in theart and, in one embodiment, provides a drug delivery system in the formof a subdermally implantable pellet that provides for controlled,sustained release of a pharmacologically active agent throughout anextended drug delivery time period. The pellet comprises an amount of anactive agent which, following subdermal implantation of at least one ofthe pellets into an individual, results in a serum level of the activeagent sufficient to provide efficacy during the extended drug deliverytime period. The pellet is bioerodible in situ, so that there is no needfor surgical removal of the pellet at the end of the drug deliveryperiod. That is, any bioerosion products are water soluble,bioresorbable, or both, so as to dissolve in or be absorbed by the body.

In one aspect of this embodiment, the drug delivery system is comprisedof more than one pellet.

In another aspect of this embodiment, the drug delivery system comprisestwo to six pellets, e.g., four or five pellets.

In another aspect of this embodiment, the pellet as a whole islipophilic, meaning that the total of any hydrophilic componentsrepresent less than 50 wt. % of the pellet.

In a related aspect, the total of any hydrophilic components representsless than 45 wt %, less than 40 wt. %, less than 35 wt. %, less than 30wt. %, less than 25 wt. %, less than 20 wt. %, less than 15 wt. %, lessthan 10 wt. %, or less than 5 wt. % of the pellet. It will thus beappreciated that the pellet may be substantially free of hydrophiliccomponents.

In another aspect of this embodiment, the pellet comprises a solid atthe temperature in the range of about about 35° C. to about 40° C. Thisensures that the pellet will be in substantially solid form in the bodyand under storage conditions. In a preferred embodiment, a hot meltpellet manufacturing method is employed, as described infra, in whichcase the pellet composition should be flowable at a selected temperaturein the range of about 50° C. to about 250° C.

In an additional aspect of this embodiment, the pellet contains anexcipient composition that includes at least one excipient. Each pelletexcipient should be (a) a water-soluble and/or bioresorbable compound,or (b) transformed in situ to water-soluble and/or bioresorbablespecies, i.e., during pellet bioerosion, or both (a) and (b). In arelated aspect of this embodiment, pellet excipients are selected fromnaturally occurring materials, where the naturally occurring materialsmay be obtained from a biological source or chemically synthesized inwhole or in part.

In another aspect of this embodiment, the pellet has an elongated form.For example, the pellet may comprise a rod-shape dosage form that may besubstantially cylindrical.

In another aspect of this embodiment, the pellet is monolithic,comprising a substantially homogeneous matrix with the active agentdispersed therein.

In another aspect of this embodiment, the pellet is composed of two ormore discrete regions each having a different composition, e.g.,compositions that differ with respect to components, component amount,component concentration, or the like. For example, the pellet may becomposed of two regions, with a first region containing the active agentand the second region containing only inactive ingredients. As anotherexample, the first region and the second region may both contain thesame active agent but with the agent present in different amounts and/orat different concentrations. As a further example, the first and secondregions may contain two different active agents.

In a related aspect, the pellet is composed of a core-and-shell type ofdosage form, where the first discrete region is the core and the seconddiscrete region is the shell. With an elongated dosage form, the firstregion may be an inner core having a length, a surface along the length,a first end, and a second end, and the second region may be an outershell enclosing the surface of the inner core along its length but notthe first end or the second end, such that the core has an exposedsurface area at the first and second ends. This type of structure may beone wherein: at least about 80 wt. % (e.g., at least about 90 wt. %,including 100%) of the active agent in the pellet is in the core(referred to herein as a “core-type” pellet); at least about 80 wt. %(e.g., at least about 90 wt. %, including 100%) of the active agent inthe pellet is in the shell (referred to herein as a “shell-type”pellet); or active agent is present in both the core and the shell withgreater than about 20 wt. % of the active agent present in each region.

In another aspect of this embodiment, the extended drug delivery timeperiod includes an effective drug delivery time period, during which theactive agent is released at a dosage sufficient to provide therapeuticefficacy, where the effective drug delivery time period is in the rangeof about three months to about four years, e.g., about six months toabout four years; about six months to about three years; or about oneyear to about three years, such as about 18 months.

In another aspect of this embodiment, the extended drug delivery timeperiod includes two time periods, a first time period that is aneffective drug delivery period as defined in the preceding paragraph,and a subsequent, second time period that is a sub-effective drugdelivery period during. That is, the pellet releases the active agentduring the first, “effective drug delivery period” at a dosagesufficient to provide therapeutic efficacy, but thereafter, during the“sub-effective drug delivery period,” the pellet continues to releasethe active agent but at a dosage that is less than sufficient to providetherapeutic efficacy (where effective and sub-effective dosagescorrelate with effective and sub-effect serum levels, respectively). Thesub-effective drug delivery period, during which the pellet continues torelease the active agent but at a dosage below an effective therapeuticdosage, is sometimes referred to as a “tail period” and, in a preferredembodiment, is at most about 12 months. In a related aspect of thisembodiment, the tail period is at most about 9 months.

In another embodiment, one or more aspects of the pharmacokineticprofile of the subdermally implantable pellet are selected and “tuned”during manufacture, using at least one pellet property selected fromwidth, length, diameter, surface area, size, composition, hardness, anddegree of crystallinity.

In a related aspect of this embodiment, the pellet includes a releaserate controlling agent as an excipient, wherein the release ratecontrolling agent has a water solubility effective to increase therelease rate of the active agent from the pellet or to decrease therelease rate of the active agent from the pellet, relative to therelease rate of the active agent from the pellet in the absence of therelease rate controlling agent.

In another related aspect of this embodiment, the pellet includes asoftening agent as an excipient. The selection of softening agent, theamount of the softening agent, or both, are selected so that the overallhardness of the pellet is as desired, e.g., for purposes ofimplantation, palpation, or the like. In a further related aspect ofthis embodiment, the softening agent is a crystallinity modulator.

In another related aspect of this embodiment, the active agent and hasan aqueous solubility of less than about 50 mg/mL.

In a related aspect of this embodiment, the active agent is selectedfrom an analgesic agent; an anti-anxiety agent; an anti-arthritic agent;an anti-asthmatic agent; an anticancer agent; an anticholinergic agent;an anticholinesterase; an anticonvulsant; an antidepressant; anantidiabetic agent; an antidiarrheal agent; an anti-emetic agent; anantihistamine; an antihyperlipidemic agent; an anti-infective agent; ananti-inflammatory agent; an antimigraine agent; an anti-obesity agent;an antipruritic agent; an antipsychotic agent; an antispasmodic agent;an agent for treating a neurodegenerative disease; a cardiovascularmedicament; a diuretic agent; a gastrointestinal medication; a hormoneor anti-hormone; a hypnotic agent; an immunosuppressive agent; aleukotriene inhibitor; a narcotic agonist or antagonist; aneurotransmitter; nicotine; a nucleic acid; a peptide drug; a nutrient;a sympathomimetic agent; a thrombolytic agent; a vasodilator; or acombination thereof

In further related aspects of this embodiment, the active agentcomprises an antipsychotic agent; an anti-inflammatory agent, e.g., anon-steroidal anti-inflammatory agent; a gastrointestinal medication,e.g., a proton pump inhibitor; an anticancer agent, e.g., ananti-metabolite, an anti-microtubule agent, a cytotoxic antibiotic, atopoisomerase inhibitor, an aromatase inhibitor, a GnRH analogue, ahormone receptor antagonist, a hormonal agent, an anti-angiogenic agent,or an anti-metastatic agent; an anti-infective agent, e.g., anantibiotic, an antiviral agent, an antifungal agent, or an antiparasiticagent; a cardiovascular medicament, e.g., an antiarrhythmic agent, anantihypertensive agent, or an anti-anginal agent; an agent for treatinga neurodegenerative disorder; a phytonutrient; a vitamin; or acombination thereof.

In another embodiment, the invention provides a method for administeringa pharmacologically active agent to a subject in a sustained releasemanner over an extended drug delivery time period, where the methodinvolves subdermally implanting a drug delivery system as describedabove into the subject and allowing the drug delivery system to remainin place throughout the extended drug delivery time period.

The invention also provides a method for making a monolithic pellet forcontrolled release of a pharmacologically active agent, comprising:comprising:

(a) providing (i) an elongated pin having a substantially cylindricalupper segment terminating in a pin tip, (ii) a pelleting tube having anupper tube opening, an opposing lower tube opening, an inner surface,and an inner diameter sized to provide a sealing fit between the innersurface and the upper segment of the pin, and (iii) a funnel having anoutlet aligned with the upper tube opening;

(b) inserting the pin tip into the lower tube opening and moving the pinupward through the tube toward the funnel until the pin tip reaches theupper tube opening;

(c) placing a molten pellet composition into the funnel, the compositioncontaining the pharmacologically active agent;

(d) partially withdrawing the pin from the tube through the lower tubeopening such that the pin tip is lowered a selected distance from theupper tube opening, thereby drawing the pellet composition into thetube; and

(e) allowing the pellet composition to cool within the tube so as toform a pellet having a pellet length corresponding to the selecteddistance and a pellet diameter defined by the inner diameter.

A method for making a core-and-shell type of pellet for controlledrelease of a pharmacologically active agent, the method comprising:

(a) providing (i) an elongated pin comprising two axially aligned,substantially cylindrical adjacent segments of different diameters, witha wider lower segment and a narrower upper segment terminating in a pintip, (ii) a pelleting tube having an upper tube opening, an opposinglower tube opening, an inner surface, and an inner diameter sized toprovide a sealing fit between the inner surface and the lower segment ofthe pin, and (iii) a funnel having an outlet aligned with the upper tubeopening;

(b) inserting the pin tip into the lower tube opening and moving the pinupward through the tube toward the funnel until the pin tip and upperpin segment protrude from the upper tube opening into the funnel,thereby bringing the lower pin segment within the tube;

(c) placing a molten shell composition in the funnel;

(d) gradually withdrawing the lower segment from the tube through thelower tube opening, thereby lowering the upper segment into the tube andsimultaneously drawing the shell composition into a concentric spacebetween the upper segment and the inner surface of the tube;

(e) allowing the shell composition to cool and harden into a shellformed around the upper segment within the concentric space;

(f) placing a molten core composition into the funnel; and

(g) gradually lowering the upper segment within the tube in a mannerthat draws the core composition into the shell, wherein the shellcomposition and/or core composition contain a pharmacologically activeagent.

The core-and-shell pellet thus formed is allowed to cool and hardenwithin the tube. The pin is then completely withdrawn and the pellet canbe removed from the tube.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (PRIOR ART) is a graph showing the extended time period duringwhich an implanted norethindrone pellet was found to releasesub-effective but detectable concentrations of the active agent (adaptedfrom Raymond et al. (1996) Fertil. Steril. 66(6):954-61).

FIG. 2A schematically illustrates a pellet manufacturing assembly usedto make a monolithic pellet of the invention, prior to drawing thepellet composition into the pelleting tube; FIG. 2B schematicallyillustrates the pellet manufacturing assembly subsequent to drawing thepellet composition into the pelleting tube.

FIG. 3A schematically illustrates a pellet manufacturing assembly usedto make a core-and-shell type pellet of the invention; FIG. 3Billustrates the core-and-shell type pellet manufacturing assembly ofFIG. 3A with the shell composition having been introduced into thefunnel above the pelleting tube; FIG. 3C illustrates the core-and-shelltype pellet manufacturing assembly of FIG. 3B with the shell materialhas been drawn down into a concentric space within the pelleting tube;FIG. 3D illustrates the core-and-shell type pellet manufacturingassembly of FIG. 3C with the core composition having been introducedinto the funnel above the pelleting tube; and FIG. 3E illustrates thecore-and-shell type pellet manufacturing assembly of FIG. 3D with thecore composition having been drawn down into the cooled shell materialwithin the pelleting tube.

FIG. 4 provides the dissolution profiles for monolithic pellet implantswith different diameters, as described in Example 1.

FIG. 5 provides the dissolution profiles for monolithic pellet implantswith different lengths, as described in Example 2.

FIG. 6 provides the dissolution profile for core-type pellets, asdescribed in Examples 3 and 4.

FIG. 7 provides the dissolution profiles for shell-type pellets ofdifferent lengths, as described in Example 5.

FIG. 8A shows the dissolution profiles of thin monolithic pelletscompared with thick monolithic pellets as also described in Example 5;FIG. 8B shows the dissolution profiles of core-type pellets comparedwith thick monolithic pellets, as also described in Example 5; FIG. 8Cshows the dissolution profiles of shell-type pellets compared with thickmonolithic pellets, as also described in Example 5.

FIGS. 9 through 12 illustrate the effect of active agent concentrationon release rate, in thick monolithic pellets (FIG. 9), thin monolithicpellets (FIG. 10), core-type pellets (FIG. 11), and shell-type pellets(FIG. 12), as described in Example 6.

FIGS. 13 through 17 illustrate the effect of excipient selection onrelease rate, as described in Example 7.

FIG. 18 illustrates the in vivo test results obtained in Example 9,showing plasma progestin levels measured at different post-implantationtime points.

FIG. 19 shows the correlation between total drug released and theexposed surface area of drug-containing regions within the pellet, asdetermined in Example 8, while FIG. 20 provides the AUC (mg*day/mL)versus amount of drug released.

FIG. 21 shows the dissolution of monolithic pellets and core-typepellets made with naproxen, as described in Example 9.

FIG. 22 shows the dissolution of monolithic pellets and core-typepellets made with methocarbamol, as described in Example 10.

FIG. 23 shows the dissolution of monolithic pellets and core-typepellets made with cholecalciferol, as described in Example 11. whileFIG. 24 shows the dissolution of monolithic pellets and core-typepellets made with acetaminophen, as described in Example 12.

FIG. 25 provides the release profiles for each of the core pelletsprepared in Examples 9-12, i.e., for naproxen, methocarbamol,cholecalciferol, and acetaminophen, while FIG. 26 shows the releaseprofiles for the corresponding monolithic pellets prepared in Examples9-12.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions and Terminology:

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by one of ordinary skill in the artto which the invention pertains. Specific terminology of particularimportance to the description of the present invention is defined below.

In this specification and the appended claims, the singular forms “a,”“an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, “an active agent” refers not onlyto a single active agent but also to two or more active agents that mayor may not be combined in a mixture; “an excipient” refers to a singleexcipient or two or more excipients, which, again, may or may not becombined in a mixture; and the like.

The term “bioerodible” is used herein in a manner synonymous with“biodegradable,” and includes any mechanism that may contribute to thegradual reduction in mass of an implanted pellet throughout an extendeddrug delivery period. Thus, a bioerodible pellet may degrade as a resultof in vivo forces interacting with the pellet surface such as shearforces; cellular action, e.g., endocytosis and cell-mediated dispersionof microscopic particles released from the pellet during cell migration;and gradual dissolution of one or more pellet components. Throughoutthis disclosure and claims, the use of the term “bioerodible” tocharacterize a subdermally implantable pellet of the invention alsoindicates that the pellet bioerodes in situ in a manner that obviatesthe need for surgical removal after completion of drug release (althoughearlier removal may sometimes be desirable for one reason or another),insofar as all pellet bioerosion products are either water soluble,bioresorbable, or both. Accordingly, the term “bioerodible,” in a firstinstance, refers to a completely bioerodible pellet, which may be, forexample, a pellet entirely composed of an active agent that is graduallyreleased in situ. In a second instance, and more typically, the term“bioerodible” refers to a pellet composed of an active agent and anexcipient composition containing one or more excipients wherein eachexcipient is (a) a water-soluble and/or bioresorbable compound, or (b)transformed in situ to water-soluble or bioresorbable species, or (c)both (a) and (b), so that all products of pellet bioerosion aredissolved or absorbed within the body, and thus naturally and benignlycleared by the body.

The term “controlled release” refers to a drug-containing formulation ordosage form, e.g., subdermal implant, which does not result in immediaterelease of the drug into an absorption pool. The term is usedinterchangeably with “nonimmediate release” as defined in Remington: TheScience and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: MackPublishing Company, 1995). “Controlled release” for the present purposeincludes “sustained release” (synonymous with “extended release”),referring to a formulation that provides for gradual release of anactive agent over an extended period of time.

The term “subdermal” to refer to the intended in situ location of theimplanted pellet means that the pellet is introduced at an interior bodylocation beneath the skin, where release of the active agent occursbeneath the skin and enters the systemic circulation, i.e., theimplantable pellets of the invention provide for “systemic” drugdelivery. The subdermally implanted pellets can additionally exhibit alocal therapeutic effect, e.g., with respect to tumors, localizedinflammation, or the like, by virtue of higher active agent levelspresent in the vicinity of the pellet. Subdermal implantation includessubcutaneous implantation as well as deeper implantation (the lattergenerally being the case with hormone replacement therapy, for example,wherein the implant is typically injected into the deeper fatty layersof the stomach or buttocks rather than subcutaneously).

The term “lipophilic” as used herein refers to a pellet or to a pelletsegment (e.g., shell or core) containing less than 50 wt. % hydrophilicmaterials, where “hydrophilic” materials in this context are materialshaving an aqueous solubility greater than about 50 mg/mL (5 wt. %). Itwill be appreciated that a pellet, core, or shell that contains 50 wt. %or more of a lipophilic active agent is lipophilic as a result, even ifthe pellet, core, or shell contains one or more hydrophilic excipients,because the hydrophilic excipients necessarily represent less than 50wt. % of the pellet.

The term “water soluble” refers to a compound having an aqueoussolubility greater than about 30 mg/mL (i.e., 3 wt. %), typicallygreater than about 50 mg/mL (i.e. 5 wt. %).

A “lipidic material” refers to a composition comprising one or morelipidic compounds that in combination represent greater than 50 wt. % ofthe lipidic material, wherein “lipidic compounds” include lipids per se,i.e., naturally occurring lipids, whether obtained from a biologicalsource or chemically synthesized in whole or in part; lipid analogs;lipid derivatives; lipid conjugates; and the like.

The term “flowable” refers to a composition that has been transformed,by the application of heat and/or other means (e.g., formation of asuspension, slurry, or the like), from a solid or substantially solidform to a composition that flows. Normally, the transformation iseffected thermally, within the context of a hot melt manufacturingprocess, in which case the flowable composition so provided is alsoreferred to herein as “molten.” The approximate temperature at which apellet, shell, or core composition undergoes this transition is referredto herein as the “transition temperature.” The transition temperaturemay be seen as a melting temperature, although since the compositionsherein are usually mixtures, composed of two or more differentcompounds, there is no definite melting point (unless characterizedusing an empirical method such as the determination of dropping point orslip point).

The term “substantially homogeneous” indicates a material in the form ofa mixture of two or more components in which the material issubstantially uniform throughout, with any two discrete regions withinthe material differing by at most about 20%, preferably by at most about10%, and most preferably by at most about 5%, with respect to a chemicalor physical property of the material, such as the presence or absence ofa component, the concentration of a component, the degree ofhydrophilicity or lipophilicity, density, crystallinity, or the like.

“Pharmacologically active” (or simply “active”), as in a“pharmacologically active” analog, derivative or other version of anactive agent, refers to a compound having the same type ofpharmacological activity as the parent compound and approximatelyequivalent in degree. Therefore, when referring to an active agent,whether specified as a particular compound (e.g., naproxen) or acompound class (e.g., a non-steroidal anti-inflammatory agent), the termused is intended to encompass not only the specified molecular entity orentities but also pharmaceutically acceptable, pharmacologically activeanalogs and derivatives thereof, including, but not limited to, salts,esters, prodrugs, conjugates, active metabolites, crystalline forms,enantiomers, stereoisomers, and other such derivatives, analogs, andrelated compounds.

In particular, as an example, when referring to a specific hormone,i.e., a progestogen or an estrogen, it is to be understood that the termnot only refers to the agent per se in unmodified form, but also refersto pharmacologically active, pharmaceutically acceptable esters of theagent. For instance, a reference to “hydroxyprogesterone”(17α-hydroxyprogesterone) includes not only hydroxyprogesterone per sebut also pharmacologically active, pharmaceutically acceptablehydroxyprogesterone esters such as hydroxyprogesterone caproate,hydroxyprogesterone acetate, and hydroxyprogesterone heptanoate.

It should also be noted that an active agent may be biologicallyobtained or partially or wholly chemically synthesized.

The terms “effective amount” and “therapeutically effective amount” ofan agent, compound, or composition refer to an amount that is nontoxicand effective for the intended purpose.

The term “approximately” in any context is intended to connote apossible variation of at most about 20%. Generally, the term connotes apossible variation of at most about 10%, preferably at most about 5%.The term “substantially” is defined in an analogous manner.

An “excipient” herein refers to any component within the drug deliverysystem that is an inactive ingredient, such that all components otherthan the active agent are referred to herein as “excipients.” Anyexcipient used should be “pharmaceutically acceptable,” meaning notbiologically or otherwise undesirable, so that that the excipient can beincorporated into a dosage form administered to a patient withoutcausing any significant undesirable biological effects or interacting ina deleterious manner with any other components of the dosage form.“Pharmaceutically acceptable” excipients herein meet the criteria setout in the Inactive Ingredient prepared by the U.S. Food and DrugAdministration, and, preferably, have also been designated “GenerallyRegarded as Safe” (“GRAS”).

By “long-term” administration is meant delivery of a drug to a subjectthroughout an extended drug delivery time period, on the order of aboutthree months to about four years or more. “Chronic” drug administrationrefers to long-term administration that typically involves treatment ofa chronic condition likely to persist in the absence of treatment, orprevention of a chronic condition likely to occur or reoccur in theabsence of drug administration.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, and improvement or remediation of damage. Unlessotherwise indicated, the terms “treating” and “treatment” as used hereinencompass prevention of symptoms as well.

As used herein, the terms “subject,” “individual,” and “patient” referto any individual, including humans and non-human mammals, for whom thepresent drug delivery system is intended and to whom an active agent isadministered as described herein. The subject may be human or anon-human animal, generally a mammal. Veterinary use of the present drugdelivery system is thus envisioned.

II. Pellet Composition:

The drug delivery system of the invention is composed of at least onesubdermally implantable, bioerodible pellet that provides forcontrolled, sustained release of an active agent contained thereinduring an extended drug delivery time period. A pellet may contain asingle active agent or two or more active agents, and with drug deliverysystems composed of two or more pellets, all pellets may contain thesame active agent or different active agents may be incorporated intodifferent pellets.

The invention is not limited with respect to particular active agents oractive agent classes. For practical purposes, however, it is generallypreferred that the active agent selected for incorporation into animplantable pellet is solid at temperatures below about 40° C. Activeagents should also have an aqueous solubility below about 50 mg/mL, morepreferably below about 30 mg/mL. In addition, potent active agents,i.e., active agents that are effective at relatively low dosages, arepreferred, insofar as a lower quantity of active agent per pellet isnecessary. This in turn minimizes the number and/or size of pelletsneeded to provide therapeutic efficacy over the effective drug deliverytime period. “Potent” active agents in the present context are generallydrugs that are effective at a daily dosage of less than about 10 mg,preferably less than 5 mg, and more preferably less than 1 mg.Optimally, potent active agents herein are therapeutically effective ata dose in the range of about 0.1 mg/day to about 0.5 mg/day.

In general, the active agent(s) herein may be selected from any of thegenerally recognized classes of pharmacologically active agents,including, without limitation: analgesic agents; anti-anxiety agents;anti-arthritic agents; anti-asthmatic agents; anticancer agents;anticholinergic agents; anticholinesterases; anticonvulsants;antidepressants; antidiabetic agents; antidiarrheal agents; anti-emeticagents; antihistamines; antihyperlipidemic agents; anti-infectiveagents; anti-inflammatory agents; antimigraine agents; anti-obesityagents; agents; antipruritic agents; antipsychotic agents; antispasmodicagents; agents for treating neurodegenerative diseases; cardiovascularmedicaments; diuretic agents; gastrointestinal medicaments; hormones andanti-hormones; hypnotic agents; immunosuppressive agents; leukotrieneinhibitors; narcotic agonists and antagonists; neurotransmitters;nicotine; nucleic acids; peptide drugs; phytonutrients; sympathomimeticagents; thrombolytic agents; vasodilators; vitamins and mineralsupplement; and combinations thereof.

Examples of preferred subclasses and specific agents therein include,without limitation, the following:

Analgesic agents, which include opioid analgesics such as alfentanil,buprenorphine, butorphanol, codeine, drocode, fentanyl, hydrocodone,hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine,oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, andtramadol; and nonopioid analgesics such as apazone, etodolac,diphenpyramide, indomethacin, meclofenamate, mefenamic acid, oxaprozin,phenylbutazone, piroxicam, and tolmetin.

Anti-anxiety agents (“anxiolytics”), which include benzodiazepines suchas alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam,halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam,prazepam, quazepam, temazepam, and triazolam; buspirone, and droperidol.

Anticancer agents, including any type of active agent that acts toeliminate, mitigate, or otherwise treat cancer. Anticancer agents thatare generally referred to as chemotherapy agents includeantimetabolites, e.g., anti-folates such as methotrexate and pemetrexed;fluoropyrimidines such as fluorouracil and capecitabine; deoxynucleosideanalogs such as cytarabine, gemcitabine, decitabine azacitidine,fludarabine, nelarabine, cladribine, clofarabine, and pentostatin; andthiopurines such as thioguanine and mercaptopurine. Other types ofchemotherapy agents are anti-microtubule agents such as paclitaxel,docetaxel, vindesine, and vinflunine; topoisomerase inhibitors such asirinotecan, topotecan, etoposide, and teniposide; and cytotoxicantibiotics such as aclararubicin, pirarubicin, mitoxantrone, mitomycin.

Another subclass of anticancer agents is used to provide any of severaltypes of hormonal therapy, where the active agents are inhibitors ofhormone synthesis, hormone receptor antagonists, or hormone supplements.Hormone synthesis inhibitors include aromatase inhibitors such asletrozole, anastrozole, exemestane, megestrol acetate,aminoglutethimide, typically used to treat breast cancer; and analogs ofgonadotropin-releasing hormone (GnRH), such as leuprorelin, goserelin,and histrelin, used in the treatment of prostate cancer. Hormonereceptor antagonists include selective estrogen receptor modulators(SERMS) such as tamoxifen, raloxifene, toremifene, and fulvestrant, aswell as anti-androgens such as flutamide and bicalutamide.

Additional anticancer agents of use herein also include anti-angiogenicagents, such bevacizumab, itraconazole, ranibuzamab, ramucirumab,prolactin, and other VEGF inhibitors; cell proliferation inhibitors suchas angiostatin, endostatin, and thrombospondin; and exogenous matrixmetalloproteinase inhibitors, such as batimastat, cipemastat, ilomastat,marimastat, MMI270, prinomastat, rebimastat, and tanomastat.

Another class of anticancer agents of use in conjunction with theinvention are hormone supplements, such as megestrol acetate,medroxyprogesterone, fluoxymesterone, and octreotide.

Anticholinergic agents, i.e., acetylcholine blockers useful in thetreatment of a number of conditions. Representative anticholinergicagents include, without limitation, atropine, scopolamine,glycopyrrolate, trihexyphenidyl, biperiden, metixene, procyclidine,profenamine, dexetimide, phenglutarimide, mazaticol, bornaprine, andtropatepine.

Anticonvulsant agents, including anti-epileptic agents, withrepresentative examples of such agents including aminobutyric acid,acetazolamide, carbamazepine, clonazepam, clorazepate, ethadione,ethosuximide, ethotoin, felbamate, foxphenytoin, gabapentin,lamotrigine, levetiracetam, mephenytoin, methylphenobarbital,oxycarbazepine, phenytoin, pheneturide, phenobarbital, phensuximide,pregabalin, primidone, progabide, rufinamide, tiagabine, topiramate,trimethadione, valproic acid, valpromide, vigabatrin, and zonisamide.

Antidepressants, including (a) tricyclic antidepressants such asamoxapine, amitriptyline, clomipramine, desipramine, doxepin,imipramine, maprotiline, nortryptiline, protryptiline, and trimipramine,(b) serotonin reuptake inhibitors such as citalopram, escitalopram,fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine, (c)monoamine oxidase inhibitors such as phenelzine, tranylcypromine, and(-)-selegiline, and (d) other, “atypical” antidepressants such asbupropion, nefazodone, trazodone, and venlafaxine.

Antiemetic agents, including, without limitation, chlorpromazine,cisapride, domperidone, granisetron, metoclopramide, ondansetron,perphenazine, prochlorperazine, promethazine, thiethylperazine, andtriflupromazine;

Antihistamines administrable in conjunction with the delivery systems ofthe invention include, without limitation, H1 antihistamines such as theH1 antagonists diphenhydramine, cetirizine, chlorpheniramine,dimenhydrinate, diphenhydramine, fexofenadine, hydroxyzine,orphenadrine, pheniramine, and doxylamine; and H2 antihistamines,including cimetidine, famotidine, lafutidine, nizatidine, ranitidine,and roxatidine.

Antihyperlipidemic agents, which include the HMG CoA reductaseinhibitors lovastatin, simvastatin, atorvastatin, pravastatin,fluindostatin, mevastatin, velostatin, and cerivastatin; bile acidsequestrants such as cholestyramine, cholestipol, colesevalam; andfibric acid derivatives such as bezafibrate, beclobrate, binifibrate,ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate,gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, andtheofibrate.

Anti-inflammatory agents, used to treat numerous indications, includeboth non-steroidal anti-inflammatory agents and steroidalanti-inflammatory agents. NSAIDS include propionic acid derivatives suchas ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen,benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen,suprofen, alminoprofen, butibufen, fenbufen and tiaprofenic acid;acetylsalicylic acid; apazone; diclofenac; difenpiramide; diflunisal;etodolac; flufenamic acid; indomethacin; ketorolac; meclofenamate;mefenamic acid; nabumetone; phenylbutazone; piroxicam; salicylic acid;sulindac; tolmetin; oxicams such as meloxicam and piroxicam; nabumetone;phenylbutazone; piroxicam; salicylates such as salsalate andacetylsalicylic acid; sulfasalazine; sulindac; tolmetin; and COX-2inhibitors such as celecoxib, rofecoxib, and valdecoxib.

Steroidal anti-inflammatory agents include corticosteroids of varyingpotency. Representative corticosteroids of lower to moderate potencyinclude hydrocortisone, hydrocortisone-21-monoesters (e.g.,hydrocortisone-21-acetate, hydrocortisone-21-butyrate,hydrocortisone-21-propionate, hydrocortisone-21-valerate, etc.),hydrocortisone-17,21-diesters (e.g., hydrocortisone-17,21-diacetate,hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate,etc.), alclometasone, dexamethasone, flumethasone, prednisolone, andmethylprednisolone. Higher potency corticosteroids, which are generallypreferred herein for reasons discussed above, include drugs such asbetamethasone, typically as betamethasone benzoate or betamethasonediproprionate; fluocinonide; prednisone; and triamcinolone, typically astriamcinolone acetonide.

Anti-infective agents: the drug delivery system and method of theinvention can be used to provide long-term sustained release of avariety of anti-infective agents, including antibiotics, antiviralagents; antifungal agents; and antiparasitic agents.

Suitable antibiotic agents include, without limitation,

(a) tetracycline antibiotics and related compounds, such aschlortetracycline, oxytetracycline, demeclocycline, methacycline,doxycycline, and rolitetracycline;

(b) macrolide antibiotics such as erythromycin, clarithromycin, andazithromycin;

(c) streptogramin antibiotics such as quinupristin and dalfopristin;

(d) beta-lactam antibiotics, including penicillins (e.g., penicillin G,penicillin VK), antistaphylococcal penicillins (e.g., cloxacillin,dicloxacillin, nafcillin, and oxacillin), extended spectrum penicillins(e.g., aminopenicillins such as ampicillin and amoxicillin, and theantipseudomonal penicillins such as carbenicillin), cephalosporins(e.g., cefadroxil, cefepime, cephalexin, cefazolin, cefoxitin,cefotetan, cefuroxime, cefotaxime, ceftazidime, and ceftriazone), andcarbapenems such as imiprenem, meropenem and aztreonam;

(e) aminoglycoside antibiotics such as streptomycin, gentamicin,tobramycin, amikacin, and neomycin;

(f) glycopeptide antibiotics such as vancomycin and teicoplanin;

(g) sulfonamide antibiotics such as sulfacetamide, sulfabenzamide,sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine,sulfamethizole, and sulfamethoxazole;

(h) quinolone antibiotics such as ciprofloxacin, nalidixic acid, andofloxacin;

(i) anti-mycobacterials such as isoniazid, rifampin, rifabutin,ethambutol, pyrazinamide, ethionamide, aminosalicylic, and cycloserine;and

(j) miscellaneous antibacterial agents such as chloramphenicol,spectinomycin, polymycin B (colistin), and bacitracin.

Antiviral agents, including antiretroviral agents, can also be deliveredusing the present systems. Representative antiviral agents include,without limitation, acyclovir, famcyclovir, ganciclovir, foscarnet,idoxuridine, sorivudine, trifluorothymidine, valacyclovir, vidarabine,didanosine, dideoxyinosine, stavudine, zalcitabine, zidovudine,amantadine, interferon alpha, ribavirin and rimantadine.

Systemic antifungal agents suitable for delivery using the presentsystem include, without limitation, itraconazole, ketoconazole,fluoconazole, and amphotericin B. Examples of antiparasitic agentssuitable herein include the broad spectrum antiparasitic medicamentnitazoxanide; antimalarial drugs and other antiprotozoal agents (e.g.,artemisins, mefloquine, lumefantrine, tinidazole, and miltefosine);anthelminthics such as mebendazole, thiabendazole, and ivermectin; andantiamoebic agents such as rifampin and amphotericin B.

Antipsychotic drugs that can be administered herein. Antipsychotic drugdelivery is a significant application of the present invention, insofaras patient compliance is commonly problematic, often with direconsequences. Examples of antipsychotic drugs that can be administeredusing the present system include (a) phenothiazines such asacetophenazine, acetophenazine maleate, chlorpromazine, chlorpromazinehydrochloride, fluphenazine, fluphenazine hydrochloride, fluphenazineenanthate, fluphenazine decanoate, mesoridazine, mesoridazine besylate,perphenazine, pipothiazine, pipothiazine palmitate, thioridazine,thioridazine hydrochloride, trifluoperazine, and trifluoperazinehydrochloride; (b) thioxanthenes such as chlorprothixene, flupenthixol,flupenthixol decanoate, thiothixene, thiothixene hydrochloride, andzuclopenthixol; (c) other heterocyclic drugs such as aripiprazole,carbamazepine, clozapine, droperidol, haloperidol, haloperidoldecanoate, iloperidol, lamotrigine, loxapine succinate, molindone,molindone hydrochloride, olanzapine, pimozide, quetiapine, paliperodone;risperidone, and sertindole; and (d) other antipsychotic agents such aslithium, valproic acid, and valproic acid esters, salts, and otherderivatives.

Preferred antipsychotic agents for long-term administration using thepresent controlled release systems include haloperidol, haloperidoldecanoate, iloperidone, flupenthixol, flupenthixol decanoate,paliperodone, olanzapine, aripiprazole, pipoxanthine, zuclopenthixol(preferably as the decanoate, acetate, or dihydrochloride), lithium,risperidone, valproic acid, sodium valproate, and lamotrigine, withhaloperidol and risperidone representing exemplary antipsychotic agentsherein, in terms of both potency and thermal stability.

As with antipsychotic agents, compliance can be a serious problem withpatients taking medication for treatment of a neurodegenerative disordersuch as Alzheimer's disease, Huntington's disease, Parkinson's disease,and amyotrophic lateral sclerosis. Active agents for treatingAlzheimer's disease and Huntington's disease are useful for treatingdementias and/or enhancing memory and learning processes, and include,for instance, donezepil, donepezil hydrochloride, physostigmine,physostigmine salicylate, tacrine and tacrine hydrochloride, whilefluoxetine and carbamazepine are used to treat Huntington's Disease.Anti-Parkinsonism drugs useful herein include amantadine, apomorphine,bromocriptine, levodopa (particularly a levodopa/carbidopa combination),pergolide, ropinirole, selegiline, trihexyphenidyl, and trihexyphenidylhydrochloride, and anticholinergic.

Cardiovascular medicaments administrable in conjunction with theinvention include antiarrhythmic agents, antihypertensive agents, andanti-anginal agents, with anti-arrhythmic agents including digoxin andbeta-blockers such as timolol, atenolol, and betaxolol, and the primaryanti-anginal agent being nitroglycerin. Antihypertensive agents include,without limitation: angiotensin-converting-enzyme (ACE) inhibitors suchas captopril, zofenopril, fosinopril, enalapril, lisinopril, benazepril,and imidapril; dihydropyridine (DHP) calcium channel blockers such asamlodipine, dihydropyridine, felodipine, nifedipine, nicardipine,nimodipine, and nisoldipine; phenylalkylamine calcium channel blockerssuch as fendiline, gallopamil, and verapamil; benzothiazepine calciumchannel blockers such as diltiazem; and angiotensin II receptorantagonists such as valsartan, losartan, irbesartan, and olmesartan;alpha blockers such as doxazosin, indoramine, phenoxybenzamine,phentolamine, prazosin, tolazoline, terazosin, trimazosin, tamsulosin,and yohimbine; and other antihypertensive agents including clonidine,apraclonidine, guanfacine, and guanabenz.

In addition to the corticosteroids identified above as anti-inflammatoryagents, other types of steroid hormones can also be advantageouslyadministered with the present drug delivery system. Examples includeprogestogens such as 21-acetoxypregnenolone, allylestrenol, anagestone17α-hydroxy-6α-methylpregn-4-en-20-one, anagestone 17α-acetate,chlormadinone, chlormadinone 17α-acetate, chloroethynyl norgestrel,cyproterone, cyproterone 17α-acetate, desogestrel, dienogest,dimethisterone (6α,21-dimethylethisterone), drospirenone(1,2-dihydrospirorenone), ethisterone (17α-ethinyltestosterone orpregneninolone), ethynerone, etynodiol diacetate (norethindroldiacetate), etonogestrel (11-methylene-levo-norgestrel;3-keto-desogestrel), gestodene, hydroxyprogesterone(17α-hydroxyprogesterone), hydroxyprogesterone caproate,hydroxyprogesterone acetate, hydroxyprogesterone heptanoate,levonorgestrel, lynestrenol, medrogestone(6,17α-dimethyl-6-dehydroprogesterone), medroxyprogesterone,medroxyprogesterone acetate, megestrol, megestrol acetate, segesteroneacetate, nomegestrol, nomegestrol acetate, norethindrone(norethisterone; 19-nor-17α-ethynyltestosterone), norelgestromin(17-deacetylnorgestimate), noretynodrel, norgestrienone, progesterone,and retroprogesterone. Progestogens within this group that are sometimespreferred include, by way of example only, desogestrel, dienogest,drospirenone, ethisterone, etonogestrel, gestodene, levonorgestrel,medroxyprogesterone, megestrol, norethindrone, norgestimate, and estersof any of the foregoing, when the compound allows for esterification(e.g., medroxyprogesterone acetate, megestrol acetate, and norethindroneacetate). Within this group, the progestogenic agents that are generallypreferred include etonogestrel and levonorgestrel.

Another example of a type of steroid that can be administered with thesystems of the invention is an estrogen, i.e., an estrogenic compound.Estrogenic compounds include synthetic and natural estrogens such as:estradiol (i.e., 1,3,5-estratriene-3,17β-diol, or “17β-estradiol”) andits esters, including estradiol benzoate, valerate, cypionate,heptanoate, decanoate, acetate and diacetate; 17α-estradiol;ethinylestradiol (i.e., 17α-ethinylestradiol) and esters and ethersthereof, including ethinylestradiol 3-acetate and ethinylestradiol3-benzoate; estriol and estriol succinate; polyestrol phosphate; estroneand its esters and derivatives, including estrone acetate, estronesulfate, and piperazine estrone sulfate; quinestrol; mestranol; andconjugated equine estrogens. Generally preferred such compounds include17β-estradiol, estetrol, estriol, estrone, ethinyl estradiol, mestranol,moxestrol, quinestrol, conjugated estrogens, and combinations thereof.

A steroid combination can also be included in the implantable pellets,for example to provide a sustained release male contraceptive system.Typically, although not necessarily, the steroid combination in thiscontext includes a progestogen, such as a progestogen identified above,and an androgenic agent. Suitable androgenic agents for incorporationinto a male contraceptive system herein include, but are not limited to:naturally occurring androgens and derivatives thereof includingandrosterone, androsterone acetate, androsterone propionate,androsterone benzoate, androstenediol, androstenediol-3-acetate,androstenediol-17-acetate, androstenediol-3,17-diacetate,androstenediol-17-benzoate, androstenediol-3-acetate-17-benzoate,androstenedione, dehydroepiandrosterone (DHEA; also termed“prasterone”), sodium dehydroepiandrosterone sulfate,4-dihydrotestosterone (DHT; also termed “stanolone”),5α-dihydrotestosterone, dromostanolone, dromostanolone propionate,ethylestrenol, nandrolone phenpropionate, nandrolone decanoate,nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolonebenzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol andtestosterone; pharmaceutically acceptable esters of testosterone and4-dihydrotestosterone, typically esters formed from the hydroxyl grouppresent at the C-17 position, including, but not limited to, theenanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate,buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprateesters; and pharmaceutically acceptable derivatives of testosterone suchas methyl testosterone, testolactone, oxymetholone and fluoxymesterone.The weight ratio of the progestogen to the androgen will typically be inthe range of about 1:5 to about 5:1, more typically in the range ofabout 1:3 to about 3:1.

Peptide drugs, including amino acids, oligopeptides, polypeptides, andproteins, can also be delivered with the present systems. Such drugsinclude coagulation modulators, cytokines, endorphins, peptidichormones, leuteinizing hormone-releasing hormone (LHRH) analogues,kinins, and enzyme inhibitors, with specific examples as follows:

Coagulation modulators, such as α1-antitrypsin, α2-macroglobulin,antithrombin III, factor I (fibrinogen), factor II (prothrombin), factorIII (tissue prothrombin), factor V (proaccelerin), factor VII(proconvertin), factor VIII (antihemophilic globulin or AHG), factor IX(Christmas factor, plasma thromboplastin component or PTC), factor X(Stuart-Power factor), factor XI (plasma thromboplastin antecedent orPTA), factor XII (Hageman factor), heparin cofactor II, kallikrein,plasmin, plasminogen, prekallikrein, protein C, protein S,thrombomodulin and combinations thereof;

Cytokines, such as transforming growth factors (TGFs), including TGF-β1,TGF-β2, and TGF-β3; bone morphogenetic proteins (for example, BMP-1,BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7, BMP-8, BMP-9); heparin-bindinggrowth factors (for example, fibroblast growth factor (FGF), epidermalgrowth factor (EGF), platelet-derived growth factor (PDGF),heparin-binding neurotrophic factor (HBNF), and insulin-like growthfactor (IGF)); connective tissue activated peptides (CTAPs), osteogenicfactors; colony stimulating factor; interferons, including interferon-α,interferon α-2a, interferon α-2b, interferon α-n3, interferon-beta, andinterferon-γ; interleukins, including interleukin-1, interleukin-2,interleukin-3, interleukin-4, interleukin-5, interleukin-6,interleukin-7, interleukin-8, interleukin-9, interleukin-10,interleukin-11, interleukin-12, interleukin-13, interleukin-14,interleukin-15, interleukin-16, and interleukin-17; tumor necrosisfactor; tumor necrosis factor-alpha; granulocyte colony-stimulatingfactor (G-CSF); granulocyte-macrophage colony-stimulating factor(GM-CSF); macrophage colony-stimulating factor; inhibins (e.g., inhibinA and inhibin B); growth differentiating factors (e.g., GDF-1); activins(e.g., activin A, activin B, and activin AB); midkine (MD); andthymopoietin;

Endorphins, i.e., peptides that activate opiate receptors, includingpharmacologically active endorphin derivatives such as dermorphin,dynorphin, α-endorphin, β-endorphin, γ-endorphin, σ-endorphin[Leu5]enkephalin, [Met5]enkephalin, substance P, and combinationsthereof;

Peptidic hormones, such as activin, amylin, angiotensin, atrialnatriuretic peptide (ANP), calcitonin (derived from chicken, eel, human,pig, rat, salmon, etc.), calcitonin gene-related peptide, calcitoninN-terminal flanking peptide, cholecystokinin (CCK), ciliary neurotrophicfactor (CNTF), corticotropin (adrenocorticotropin hormone, ACTH),corticotropin-releasing factor (CRF or CRH), follicle-stimulatinghormone (FSH), gastrin, gastrin inhibitory peptide (GIP),gastrin-releasing peptide, glucagon, gonadotropin-releasing factor (GnRFor GnRH), growth hormone releasing factor (GRF, GRH), human chorionicgonadotropin (hCG), inhibin A, inhibin B, insulin (derived from beef,human, pig, etc.), leptin, lipotropin (LPH), luteinizing hormone (LH),luteinizing hormone-releasing hormone (LHRH), lypressin,α-melanocyte-stimulating hormone, β-melanocyte-stimulating hormone,γ-melanocyte-stimulating hormone, melatonin, motilin, oxytocin(pitocin), pancreatic polypeptide, parathyroid hormone (PTH), placentallactogen, prolactin (PRL), prolactin-release inhibiting factor (PIF),prolactin-releasing factor (PRF), secretin, somatostatin, somatotropin(growth hormone, GH), somatostatin (SIF, growth hormone-releaseinhibiting factor, GIF), thyrotropin (thyroid-stimulating hormone, TSH),thyrotropin-releasing factor (TRH or TRF), thyroxine, triiodothyronine,vasoactive intestinal peptide (VIP), and vasopressin (antidiuretichormone, ADH);

Analogues of LHRH, such as buserelin, deslorelin, fertirelin, goserelin,histrelin, leuprolide (leuprorelin), lutrelin, nafarelin, tryptorelinand combinations thereof;

Kinins, such as bradykinin, potentiator B, bradykinin potentiator C, andkallidin and combinations thereof; and

Enzyme inhibitors, such as leupeptin, chymostatin, pepstatin, renininhibitors, and the like.

In addition to peptide drugs, other types of biomolecules can also beadministered with the present systems, particularly nucleic acids,including gene fragments, oligonucleotides and polynucleotides,antisense oligonucleotides and polynucleotides, oligonucleotides andpolynucleotides containing one or more nonnatural amino acids and/ornonnatural internucleotide linkage, or any other nucleic acid havingbiological activity or other benefit. Other biomolecules of interestherein include lipids, lipoproteins, lipopolysaccharides,polysaccharides, and the like.

Other examples of active agents and active agent subclasses that areuseful in conjunction with the present invention include, withoutlimitation, the following:

anti-diarrheal agents such as loperamide and cholestyramine;

muscle relaxants (antispasmodic agents) such as methocarbamol,carisoprodol, cyclobenzaprine, metaxalone, mebeverine, papaverine;

anti-ulcer and other gastrointestinal drugs such as ranitidine and theproton pump inhibitors omeprazole, dexlansoprazole, lansoprazole, andesomeprazole;

appetite suppressants such as dextroamphetamine, diethylpropion,mazindol, and phentermine;

hypnotics and sedatives, such as clomethiazole, ethinamate, etomidate,glutethimide, meprobamate, methyprylon, zolpidem, and barbiturates(e.g., amobarbital, apropbarbital, butabarbital, butalbital,mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital,thiopental);

synthetic hormones such as levothyroxine;

sympathomimetic agents, i.e., central nervous system stimulants, such asagents for treating attention deficit disorder (ADD) and attentiondeficit hyperactivity disorder;

neurotransmitters, such as GABA (γ-aminobutyric acid), glycine,acetylcholine, dopamine, epinephrine, 5-hydroxytryptamine, serotonin,enkaphalins and related opioid peptides as above, and catecholamines;

narcotic agonists and antagonists such as naloxone, naltrexone,nalorphine, nalmefene, levalorphan; and

other agents for treating addiction disorders, such as disulfiram,nicotine, bupropion, varenicline, disulfiram, calcium carbimide,acamprosate, buprenorphine, methadone, levacetylmethadol, lofexidine,betahistine, cinnarizine, flunarizine, acetylleucine, gangliosides andganglioside derivatives, tirilazad, riluzole, xaliproden, hydroxybutyricacid, and amifampridine.

In addition to pharmacologically active agents typically thought of aspharmaceuticals, other types of active agents referred to herein as“nutrients” can also be administered using the present delivery systems.Nutrients include vitamin, mineral and nutritional supplements, and thelike.

Vitamins, minerals, and other nutritional supplements are naturallypresent as trace organic substances that are required in the diet, andinclude, without limitation, thiamin, riboflavin, nicotinic acid,pantothenic acid, pyridoxine, biotin, folate, vitamin B₁₂, vitamin A,vitamin D, vitamin E and vitamin K. Also included within the term“vitamin” are the coenzymes thereof, such as thiamine pyrophosphates(TPP), flavin mononucleotide (FMM), flavin adenine dinucleotide (FAD),nicotinamide adenine dinucleotide (NAD), nicotinamide adeninedinucleotide phosphate (NADP), Coenzyme A (CoA), Coenzyme Q (CoQ),pyridoxal phosphate, biocytin, tetrahydrofolic acid, and coenzyme B₁₂.The term “vitamin” also includes choline and carnitine. The term“mineral” refers to inorganic substances that are required in the humandiet, and includes, without limitation, calcium, magnesium, iron, zinc,selenium, copper, manganese, chromium, molybdenum, etc. Othernutritional supplements include amino acids, terpenoids, curcumin,resveratrol, lignans, carnitine, carnosine, carotene, choline,chondroitin sulfate, coenzyme Q10, creatine, dehydroepiandrosterone,5-hydroxytryptophan, indole-3-carbinol, methyl sulfonylmethane,phospholipids, phytosterols, essential fatty acids (e.g., omega-3 fattyacids), green tea polyphenols, quercetin and other flavonoids,S-adenosylmethionine, theobromine, and tocotrienols, among others.Further examples of suitable nutrients include those listed in Handbookof Nutraceuticals and Functional Foods, Robert E. C. Wildman, Ed., CRCPress (2001).

The amount of the pharmacologically active agent in a drug deliverysystem of the invention comprising a subdermally implantable pellet isselected to result in serum levels of the agent sufficient to providetherapeutic efficacy during the effective drug delivery time period,taking the release rate, length of the intended drug delivery timeperiod, and specific active agent into account. Another consideration iswhether the intended therapeutic effect includes a local therapeuticeffect. That is, when the system is implanted in the region of anindividual tumor, an isolated site of inflammation, or the like, theintention is to provide higher levels of active agent in the vicinity ofthe implant, which in turn impacts on the amount of active agent to beincorporated into a pellet. It should be noted that although the drugdelivery system may be composed of only one subdermally implantablepellet, it may also be composed of multiple pellets, e.g., two to sixpellets, such as four or five pellets. When the drug delivery system iscomposed of more than one pellet, the number of pellets implanted isalso taken into account in determining the amount of active agent toincorporate into a single pellet. The optimum amount is preferablycalculated for a drug delivery time period in the range of about threemonths to about four years, e.g., in the range of about six months toabout four years; in the range of about six months to about three years;and in the range of about one year to about three years, for instanceabout 18 months.

Drug loading may be in the range of about 20 wt. % to about 100 wt. %.,preferably in the range of about 50 wt. % to about 99 wt. %, morepreferably in the range of about 75 wt. % to about 95 wt. %. Theaforementioned ranges pertain to the percentage of an active agent in amonolithic pellet, or, for a core-type pellet or a shell-type pellet,the percentage of the active agent in the shell or core, respectively.Optimal drug loading may approximate 85 wt. %. The degree of drugloading can be altered to vary drug release profile as desired. As shownin Example 7, increasing the fraction of active agent in the pelletgenerally results in an increase in drug release rate.

The pellets may be wholly composed of active agent, but generally, andpreferably, contain an excipient composition as well, where theexcipient composition may be a single excipient or it may include two ormore excipients. Excipients for incorporation into the present pelletsalong with the active agent should be selected so as to avoidcompromising the bioerodibility of the pellet as a whole. This meansthat any excipients should be bioresorbable, water soluble, or both,and/or degrade or otherwise transform in vivo, during bioerosion of thepellet, to bioresorbable and/or water-soluble species. Preferredexcipients are naturally occurring compounds, which may be obtained froma biological source or chemically synthesized in whole or in part. Oneor more excipients may be hydrophilic, providing that the pellet as awhole is still lipophilic. For core-type pellets and shell-type pellets,both the core and the shell should be lipophilic, meaning that the coreand shell each contain less than 50 wt. % hydrophilic materials,preferably less than 45 wt %, less than 40 wt. %, less than 35 wt. %,less than 30 wt. %, less than 25 wt. %, less than 20 wt. %, less than 15wt. %, less than 10 wt. %, or less than 5 wt. % of the pellet.“Hydrophilic” materials, as noted previously, are materials having anaqueous solubility of at least about 3 wt. %, e.g., at least about 5 wt.%, or the like. For example, a pellet, core, or shell that contains alipophilic active agent, with the lipophilic active agent representingat least 50 wt. % of the pellet, core, or shell, respectively, isnecessarily lipophilic, insofar as the total hydrophilic componentsrepresent less than 50 wt. % of the pellet, core, or shell composition.

Excipients may or may not be solid at body temperature and under storageconditions, so long as: (1) the pellet as a whole is substantially solidat body temperature and during storage, i.e., at temperatures in therange of about 35° C. to about 40° C.; and (2) the pellet composition isflowable at a selected temperature in the range of about 50° C. to about250° C., particularly when a hot melt manufacturing technique—such asthe manufacturing process described herein—is used. In addition,excipients should be selected so that the pellet does not fracture orbreak during or after implantation. This may require inclusion of asoftening agent as an excipient, e.g., lecithin. However, the pelletshould still be hard enough so that it can be palpated afterimplantation, to confirm or determine location.

Suitable excipients include, but are not limited to, lipidic compounds,e.g., lipids per se, including naturally occurring lipids and lipidsthat are chemically synthesized in whole or in part; lipid analogs;lipid derivatives; lipid conjugates; and the like. Naturally occurringlipids and readily hydrolyzable esters of naturally occurring lipids aregenerally preferred lipidic excipients, insofar as such compoundsfacilitate bioabsorption and bioerosion to nontoxic molecularcomponents. For example, a lipidic excipient may be a sterol, a sterolester, or a combination thereof, including, without limitation,cholesterol, 7-dehydrocholesterol, cholestatrienol, cholestanol,cholesteryl acetate, desmosterol, dehydroergosterol, thiocholesterol,3-keto-delta-5-cholestene, 7-methylenecholesterol, epicholesterol,lathosterol, lanosterol, dihydrocholesterol, 25-hydroxycholesterol,cholestane, cholestane diol, cholest-4-en-3-one, and zymosterol. In someembodiments, cholesterol is a preferred lipidic excipient herein.

Other lipidic compounds that can serve as excipients herein include, butare not limited to, the following: phospholipids such as phosphorylateddiacyl glycerides, particularly phospholipids selected from the groupconsisting of diacyl phosphatidylcholines, diacylphosphatidylethanolamines, diacyl phosphatidylserines, diacylphosphatidylinositols, diacyl phosphatidylglycerols, diacyl phosphatidicacids, and mixtures thereof, wherein each acyl group contains about 10to about 22 carbon atoms and is saturated or unsaturated; fatty acidssuch as isovaleric acid, valeric acid, caproic acid, enanthic acid,caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid,palmitic acid, stearic acid, arachidic acid, behenic acid, lignocericacid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid;lower fatty acid esters comprising esters of the foregoing fatty acids,wherein the carboxylic acid group of the fatty acid is replaced with anester moiety —(CO)—OR wherein R is a C₁-C₃ alkyl moiety optionallysubstituted with one or two hydroxyl groups; fatty alcoholscorresponding to the aforementioned fatty acids, wherein the carboxylicacid group of the fatty acid is replaced by a —CH₂OH group; glycolipidssuch as cerebroside and gangliosides; oils, including animal oils suchas cod liver oil and menhaden oil, and vegetable oils such as babassuoil, castor oil, corn oil, cottonseed oil, linseed oil, mustard oil,olive oil, palm oil, palm kernel oil, peanut oil, poppyseed oil,rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower seedoil, tung oil, or wheat germ oil; and waxes, i.e., higher fatty acidesters, including animal waxes such as beeswax and shellac, mineralwaxes such as montan, petroleum waxes such as microcrystalline wax andparaffin, and vegetable waxes such as carnauba wax.

A lipidic excipient may also be incorporated into the pellets in acombination or mixture of two or more excipients (including mixtures oftwo or more lipidic excipients), for example having different aqueoussolubilities and/or with one of the excipients selected to serve aparticular purpose (e.g., functioning as a softening agent). Forexample, a pellet may contain a combination of a lipidic excipienthaving a first aqueous solubility and a second excipient, which may ormay not be lipidic, having a second aqueous solubility, where the firstaqueous solubility is lower than the second aqueous solubility by atleast 5%, typically by at least 10%. The weight ratio of the lesssoluble excipient to the more soluble excipient may be in the range ofabout 2:1 to about 100:1, more typically in the range of about 3:1 toabout 50:1, and optimally about 3.5:1 to about 25:1, e.g., 4:1. Theexamples herein describe such excipient compositions, whereincholesterol serves as the lipidic excipient with a first aqueoussolubility and lecithin or a component thereof (e.g.,phosphatidylcholine) serves as the second excipient.

Additional excipients that can be incorporated into the pellets insteadof, or in addition to, a lipidic excipient as described above, include,without limitation, phospholipids and phospholipid mixtures, e.g.,lecithin (a phospholipid mixture) and glycerophospholipids such asphosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, andphosphatidylserine; polyethylene glycols (PEGs) of different molecularweights, e.g., PEG-300, PEG-1000, PEG-4000, PEG-6000, and PEG-8000; PEGfatty acid esters such as PEG laurates, oleates, stearates, and thelike; other gradually erodible synthetic polymers such as polylactides,polyglycolides, polycaprolactones, polyanhydrides, polyurethanes,polyesteramides, polyorthoesters, polyvinylpyrrolidone, andpolyhydroxycellulose; polymers typically used to prepare hydrogels,e.g., polyvinyl alcohol, poly(hydroxyethyl methacrylate), andpolyacrylic acid; glycerine and glycerinated gelatin; chitin andchitosan; and lower molecular weight excipients such as propyleneglycol.

If desired, a radio-opaque material can be incorporated into the presentdrug delivery systems in order to enable X-ray visualization of theimplanted pellets. Suitable radio-opaque materials for this purpose areknown in the art and include, for instance, barium sulfate, titaniumoxide, bismuth oxide, tungsten, and iodinated contrast agents (i.e.,contrast agents based on the 2,4,6-triiodobenzene structure), withbarium sulfate more commonly used. Any such radio-opaque material willgenerally represent in the range of about 2.5 wt. % to about 30 wt. % ofa pellet, more typically about 2.5 wt. % to about 15 wt. % of a pellet.

III. Physical and Pharmacokinetic Attributes of the Pellet:

The pellets herein can be of any size, shape or structure that allow forease of manufacture and implantation, and that contribute to or at leastdo not detract from the desired pharmacokinetic properties. Generally,for ease of manufacture and implantation, the pellets are rod-shaped,i.e., approximately cylindrical, with length, width, surface area, etc.,selected to provide specific pharmacokinetic or other properties, suchas drug release rate, drug release profile (i.e., the change in releaserate over time), length of the effective drug delivery period, length ofany tail period, and the like.

An elongated pellet of the invention may be substantially cylindrical.Such pellets will generally have a length in the range of about 2.0 mmto about 12.0 mm, and a diameter in the range of about 1.0 mm to about3.5 mm. Typically, pellet length is in the range of about 3.5 mm toabout 7.0 mm, with pellet diameter in the range of about 1.0 to about3.2. In a preferred embodiment, the pellet length is in the range ofabout 4.0 mm to about 6.5 mm and the pellet diameter is in the range ofabout 1.3 mm to about 3.0 mm. Exemplary pellet dimensions thus include:diameter 2.8 mm, length 6.0 mm; diameter 2.8 mm, length 4.5 mm; diameter2.8 mm, length 4.0 mm; diameter 1.7 mm, length 4.0 mm. Additionalexamples are given below.

In one embodiment, the pellet is monolithic, such that the pellet iscomprised of a substantially homogeneous matrix with thepharmacologically active agent is dispersed therein, where“substantially homogeneous” is defined in Part (I) of this section. Insuch a case, the pellet may be essentially amorphous, or it may becrystalline or partially crystalline, preferably without any interiorvoids. To check a monolithic pellet for substantial homogeneity, thepellet can be divided into several, e.g., three to six, subsections, andeach subsection weighed and dissolved in a known amount of solvent. Eachdissolved subsection can then be analyzed using a standard technique,e.g., HPLC, and the relative quantities of components determined andcompared to the results in the other subsections.

A standard monolithic pellet will have dimensions as described above.

Monolithic pellets generally have a density in the range of about 0.75g/cm³ to about 1.25 g/cm³, as do pellets composed of two or morediscrete regions, e.g., cores and shells in core-type and shell-typepellets herein. More typically, monolithic pellets typically have adensity in the range of about 0.90 g/cm³ to about 1.10 g/cm³, and mosttypically in the range of about 0.95 g/cm³ to about 1.05 g/cm³.

In another embodiment, the pellet is composed of two or more discreteregions each having a different composition. That is, compositions indifferent regions may differ with respect to components of thecomposition, component amount, component concentration, or the like. Forexample, the pellet may be composed of a first region containing thepharmacologically active agent and a second region containing onlyinactive ingredients, i.e., excipients. As another example, the firstand second region may contain the same pharmacologically active agent,but in different amounts and/or present at different concentrations.Discrete regions may also contain different active agents.

A preferred pellet structure composed of two or more discrete regions isa core-and-shell type of dosage form, where the first region is an innercore and the second region is a shell that partially or entirelyencloses the core. With an elongated dosage form such as a cylindricalpellet, the first region may be an inner core having a length, a surfacealong the length, a first end, and a second end, and the second regionmay be an outer shell enclosing the surface of the inner core along itslength but not the first end or the second end, such that the core hasexposed surface area at the first and second ends. This type ofstructure may be one wherein: at least about 80 wt. % (e.g., at leastabout 90 wt. %, such as 100%) of the active agent in the pellet is inthe core (referred to herein as a “core-type” pellet); at least about 80wt. % (e.g., at least about 90 wt. %, such as 100%) in the pellet is inthe shell (a “shell-type” pellet); or active is present in both the coreand the shell with greater 20 wt. % of the active present in eachregion. In one embodiment, a core-type pellet is composed of an inactiveshell with 100% of the active in the core. In another embodiment, ashell-type pellet is composed of an inactive core with 100% of theactive in the shell.

Typical dimensions for core-shell structures, including core diameterand shell thickness, are as follows: core diameter, about 1.0 mm toabout 2.0 mm, shell thickness about 0.3 mm to about 1.0 mm, and lengthabout 4 mm to about 6.5 mm. Specific examples of core/shell structuredimensions include, without limitation: core diameter 1.7 mm, shellthickness 0.6 mm, length 4.5 mm; core diameter 1.9 mm, shell thickness0.9 mm, length 4.5 mm; core diameter 1.7 mm, shell thickness 0.6 mm,length 5.5 mm; and core diameter 1.9 mm, shell thickness 0.9 mm, length5.5 mm.

The inactive region of a core-type pellet or a shell-type pellet,whether shell or core, is composed of a bioerodible excipientcomposition as described earlier herein, with the inactive regioncontaining less than about 20 wt. %, e.g., less than about 10 wt. %, ofthe total amount of active agent in the pellet. The pharmacologicallyactive region of a core-type pellet or a shell-type pellet, i.e., theregion containing at least about 80 wt. % (e.g., at least about 90 wt.%, such as 100%) of the total amount of active agent in the pellet, maybe entirely composed of the active agent, but is usually a mixture of abioerodible excipient composition, as defined previously, and the activeagent, where the active agent is dispersed within a matrix defined bythe bioerodible excipient composition. The excipient composition of theinactive region and the excipient composition of the pharmacologicallyactive region may or may not be the same, with respect to the number,type, and/or concentration of individual excipients.

Representative examples of shell and core drug delivery systems of theinvention include, without limitation, the following:

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % cholecalciferol;

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % naproxen;

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % methocarbamol;

Monolithic pellets 1.7 mm in diameter and 4.0 mm in length, containing85 wt. % acetaminophen;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % cholecalciferol;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % naproxen;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % methocarbamol;

Monolithic pellets 1.7 mm in diameter and 4.5 mm in length, containing95 wt. % acetaminophen;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % cholecalciferol;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % naproxen;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % methocarbamol;

Monolithic pellets 1.7 mm in diameter and 3.5 mm in length, containing75 wt. % acetaminophen;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % cholecalciferol;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % naproxen;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % methocarbamol;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing85 wt. % acetaminophen;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % cholecalciferol;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % naproxen;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % methocarbamol;

Monolithic pellets 2.8 mm in diameter and 6.0 mm in length, containing95 wt. % acetaminophen;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % cholecalciferol;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % naproxen;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % methocarbamol;

Monolithic pellets 2.8 mm in diameter and 5.5 mm in length, containing75 wt. % acetaminophen;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % cholecalciferol;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % naproxen;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % methocarbamol;

Monolithic pellets 2.8 mm in diameter and 4.5 mm in length, containing85 wt. % acetaminophen;

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % cholecalciferol;

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % naproxen;

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % methocarbamol; and

Monolithic pellets 2.8 mm in diameter and 4.0 mm in length, containing75 wt. % acetaminophen.

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % naproxen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.5 mm in length, with the shell composed of85 wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % naproxen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the shell composed of85 wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % naproxen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the shell composed of85 wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % naproxen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 6.0 mm in length, with the shell composed of85 wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the core composed of 97 wt. % cholesterol and 3wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % naproxen, 12 wt. % cholesterol, and 3 wt. % phosphatidylcholine,and the shell composed of 97 wt. % cholesterol and 3 wt. %phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.5 mm in length, with the core composed of 85wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % naproxen, 12 wt. % cholesterol, and 3 wt. % phosphatidylcholine,and the shell composed of 97 wt. % cholesterol and 3 wt. %phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 4.0 mm in length, with the core composed of 85wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % cholecalciferol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % naproxen, 12 wt. % cholesterol, and 3 wt. % phosphatidylcholine,and the shell composed of 97 wt. % cholesterol and 3 wt. %phosphatidylcholine;

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % methocarbamol, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine; and

Shell/core pellets with a core 1.6 mm in diameter, a shell 0.6 mm inthickness, and the pellet 5.0 mm in length, with the core composed of 85wt. % acetaminophen, 12 wt. % cholesterol, and 3 wt. %phosphatidylcholine, and the shell composed of 97 wt. % cholesterol and3 wt. % phosphatidylcholine.

In one embodiment, the tail period is at most about 12 months,preferably at most about 9 months, more preferably at most about 6months, and ideally at most about 3 months. This contrasts with tailperiods observed with prior implants, such as those described by Raymondet al. (1996) Fertil. Steril. 66(6):954-61), illustrated in FIG. 1(prior art).

Various parameters can be adjusted to alter one or more other aspects ofa pellet's pharmacokinetic profile, such aspects including, by way ofexample, release rate, release profile, duration of the extended drugdelivery time period, and duration of the tail period. For instance, therate of drug release can be controlled both by modulating the aqueoussolubility of the pellet composition and by controlling the surface areaof the pellet, as it is the pellet surface that is exposed to in vivoerosive forces. With monolithic implants, narrower and longer pelletsgenerally have a shorter tail period. Monolithic thin pellets withlength-to-width ratios (i.e., length-to-radius ratios for substantiallycylindrical pellets) greater than about 5:1 provide for a gradual,evenly decreasing release rate. The release rate of active agent from amonolithic pellet can be controlled by the bioerosion rate of theexcipient composition, made tunable using excipients with differentaqueous solubilities, as alluded to earlier herein. That is, anexcipient composition composed entirely of a lipidic material such ascholesterol will tend to bioerode more slowly than an excipientcomposition composed of a mixture of cholesterol and a second excipienthaving higher aqueous solubility, e.g., a selected phospholipid. Therate of release can thus be controlled by varying the relative amountsof a more water-soluble excipient and a less water-soluble excipient inan excipient composition.

For substantially cylindrical core/shell pellets composed of a slowlydissolving core and a more quickly dissolving shell that contains mostor all of the active agent, the drug release profile abruptly ends aserosion from the lateral face breaks through to the underlying core.Unlike monolithic pellets, the exposed surface area of thedrug-containing shell approaches a non-zero value as it erodes, thusavoiding the release tail. In these drug-containing shell pellets, therate of drug release is controlled by the rate of shell bioerosion andby the pellet length. The duration of drug release is controlled by theshell thickness.

Placing the active agent in the core instead of the shell can alsoeliminate the tail if the rate of core erosion is significantly fasterthan that of the shell. Here, the exposed drug-containing surface isonly at the cylinder bases and drug release remains relatively constantuntil the core erodes out of the longer-lasting shell. The shell andcore release rates are tuned with the proper addition of a lipid withhigher aqueous solubility than cholesterol per se, so that erosion fromthe lateral face of the shell does not allow breakthrough before thepellet core is fully released. To achieve this result, the shellthickness divided by the shell erosion rate must be greater than orequal to the core length divided by the core erosion rate. In thesedrug-containing core systems, the rate of drug release is dependent uponthe rate of core dissolution and the surface area of the core bases, andthe duration of release is controlled by the pellet length. Anadditional benefit of a drug-containing core can be approximatelyzero-order drug release.

IV. Male Contraception:

In administering an active agent combination to male subjects to providelong-term contraception, one or more subdermally implantable pellets aremanufactured containing a combination of a progestogen and an androgen,as explained in Part II of this Detailed Description. At the outset, thenumber of pellets to be implanted is determined, taking into account theparticular active agents, the predetermined release rate, the intendeddrug delivery time period, and other factors within the knowledge of themedical practitioner prescribing or administering the contraceptivesystem.

The pellet or pellets are then subdermally implanted, usually in theupper arm, forearm, or thigh, and allowed to remain in place. Since thepellets are bioerodible, there is no need for surgical removal, althoughthe pellets can be surgically removed, if desired, at some point priorto complete bioerosion. The male subject is generally human, but thesecontraceptive implants can also be used in non-human animals.

V. Other Methods of Use:

The bioerodible, implantable pellets of the invention are useful inproviding controlled release delivery of a pharmacologically activeagent to patients for any purpose for which the incorporated activeagent is intended.

As one example, the present drug delivery system is useful in treating asubject who requires chronic dosing with an antipsychotic medication,such as a subject suffering from bipolar disorder or schizophrenia.Chronic drug therapy in this context has been associated with very lowpatient compliance, especially when an individual's mood improves andpatients may no longer feel they need the medication. Non-adherence isthe most important predictor of re-hospitalization for psychoticdisorders. The present drug delivery system eliminates the problem ofpatient compliance insofar as chronic administration, i.e.,administration throughout an effective drug delivery period that can beas long as four years or more, precludes the need for regularself-administration by patients. Exemplary antipsychotic agents foradministration to patients using the delivery system of the inventioninclude, without limitation, haloperidol, haloperidol decanoate,iloperidone, flupenthixol, flupenthixol decanoate, paliperodone,olanzapine, aripiprazole, pipoxanthine, zuclopenthixol (preferably asthe decanoate, acetate, or dihydrochloride), lithium, risperidone,valproic acid, sodium valproate, and lamotrigine, with haloperidol andrisperidone particularly preferred as explained in Part II of thisDetailed Description.

Compliance problems have also been noted in antiviral therapy, andparticularly with antiretroviral therapy, as dosing regimens arecomplicated, often involving multiple active agents administered atdifferent times throughout the day. In the management of HIV/AIDS, forinstance, current options involve regular dosing with at least threedifferent medications belong to at least two classes of antiretroviralagents: a non-nucleoside reverse transcriptase inhibitor (NNRTI) such asefavirenz, nevirapine, delavirdine, etravirine, or rilpivirine; plus twonucleoside analog reverse transcriptase inhibitors, such as zidovudine(AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), tenofovir(TDF), lamivudine (3TC), and/or emtricitabine. At some point in diseaseprogression, or as the aforementioned regimen loses effectiveness, thedosing regimen is further changed or complicated by addition of aprotease inhibitor to the combination or substitution of a proteaseinhibitor for one of the active agents. As above, using the implantablepellets of the invention to deliver these drug combinations at requiredlevels on a long-term basis precludes the need for regularself-administration by patients and therefore eliminates all risk ofnon-compliance.

In another example of an area in which the present invention fulfills asignificant need, the present drug delivery systems are used in thelong-term administration of anti-inflammatory agents, for example in thetreatment of a chronic arthritic condition, an immune system disordersuch as systemic lupus erythematosus, or other conditions, disorders, ordiseases responsive to ongoing anti-inflammatory therapy. Thepossibility of patient compliance problems is eliminated, and theadverse effects commonly seen with orally administered anti-inflammatorymedications are avoided. The present systems can be used with a host ofanti-inflammatory agents, including, without limitation, thoseincorporated into the implants prepared in the Examples (naproxen andacetaminophen).

As another example, the present drug delivery system is useful intreating a subject suffering from epilepsy and in need ofanti-convulsive therapy. One of the more commonly prescribedanti-convulsant drugs, carbamazepine, an active agent that is associatedwith erratic oral absorption and contra-indicated for patients withgastrointestinal conditions and disorders. Administering carbamazepineusing the present system would avoid the adverse effects associated withoral administration while still providing an effect dose over anextended drug delivery period.

As a further example, the invention finds utility in the treatment ofmany different types of cancer by providing a means for long-termadministration of any of a number of different classes of anti-canceragents. It may be advantageous, in some instances, to implant the drugdelivery pellet near a tumor, so that the tumor benefits from higherconcentrations of anti-cancer agent in the region of the implant. Thisis particularly useful with tumors that tend to respond poorly tosystemic chemotherapy, such as sarcomas, particularly osteosarcomas,brain cancers, and prostate cancers. Examples of anti-cancer agentsincorporated into the drug delivery pellets in this context include,without limitation, 5-fluorouracil, paclitaxel, cyclophosphamide, andthalidomide. In an approach to treating male hormone cancers such asprostate cancer, the pellets of the invention can be used in thelong-term administration of leuprolide acetate, and LHRH agonist, a drugthat is commonly prescribed for at least a year. Leuprolide acetateimplants can also be used to treat breast cancer, endometriosis, uterinefibroids, and early puberty, by reducing a subject's testosteronelevels. Treatment of female hormone cancers, such as breast cancer,cervical cancer, uterine cancer, and the like, is also simplified withthe present systems insofar as commonly prescribed drugs for thesecancers—such as aromatase inhibitors (e.g., letrozole and arimidex) andestrogen receptor blockers (such as tamoxifen)—are currently takenorally on a daily basis for five to ten years.

As a further example, the invention is useful for the chronicadministration of vitamins, supplements that many people do not considerimportant and therefore fail to take as necessary. Fat soluble vitaminssuch as Vitamin D and Vitamin K2 are of particular interest, insofar aspatients taking statins (i.e., HMG CoA reductase inhibitors prescribedas antihyperlipidemic agents or for other indications) may have reducedK2 levels (statins reduce production of K2 by the body), and many peopleare deficient in K2 for other reasons, and also deficient in Vitamin D.Both are important to treat and/or prevent atherosclerosis, osteopenia,osteoporosis, and other conditions; for instance, it has recently beenreported that pregnant women with low Vitamin D levels are at anelevated risk for conceiving a child with autistic traits.

Accordingly, the subdermally implantable pellets of the invention areuseful in providing for the ongoing, controlled release of apharmacologically active agent for a host of indications with a widevariety of active agents and active agent classes. It is to beunderstood that the invention is not limited to the conditions,disorders, diseases, and active agents explicitly mentioned herein, andthat other specific agents and indications with which the presentinvention is useful will be apparent to those of ordinary skill in theart and/or are described in the relevant texts and literature.

VI. Pellet Implantation:

One or more controlled release pellets of the invention are subdermallyimplanted into a subject for long-term, sustained release administrationof the pharmacologically active agent therein, as described throughoutthis specification. Generally, although not necessarily, thedrug-containing pellets are positioned just under the skin. Methods anddevices for insertion and positioning of subdermal implants are known inthe art, and any suitable method or device can be used in conjunctionwith the invention. Examples of suitable implantation devices includetrocar-like inserters, other commercially available implantationdevices, and devices described in the patent literature such as in U.S.Pat. Nos. 4,223,674; 6,964,648; 7,214,206; 7,510,549; 7,850,639; andInternational Patent Publication No. WO 98/13092 A1. Other suitableimplantation devices will be apparent to those skilled in the art and/orare described in pertinent texts and literature. Subdermal implantationmethods and devices should be non-irritating and non-sensitizing, andshould work relatively quickly.

VII. Pellet Manufacture:

Any method to manufacture the present pellets may be implemented so longas the compositional and physical requirements of the pellets so madeare met. Manufacturing methods include, for example, compressionmolding, molding, hot melt extrusion, injection molding, and hot meltmolding.

One example of a preferred method to manufacture the present pellets isa variation of the hot melt molding process, a hot melt “drawing”process that uses a pin to pull a substantially homogenous mixture ofpellet substrate material out of a heated reservoir and into a heatedchannel, or tube, composed of an inert, heat-resistant material such aspolytetrafluoroethylene (“PTFE”). The pellet material can then be cooledunder “channel capping” conditions, i.e., conditions that allow thepellet to fully form without internal cavities or sinks. Channel cappinginvolves withdrawal of the elongated pin from the interior of the formedpellet, when still warm, in a gradual manner that allows the interior ofthe pellet to fuse and contract.

The method can be modified to make core-type and shell-type pellets, byfirst drawing molten shell material from the reservoir into the channeland allowing it to harden somewhat, forming a shell between a narrow pinextension and the interior of the channel. After allowing some cooling,and wiping the reservoir clean before continuing, molten core materialfrom the reservoir is then drawn into the solidified shell. After abrief cooling period, the solid core-and-shell pellet can be pushed outof the channel/tube.

FIG. 2A and 2B illustrate a pellet manufacturing assembly that can beused to make monolithic pellets of the invention. As shown in FIG. 2A,the assembly 10 includes an elongated pin having a body 12, a tip 14,and a substantially cylindrical upper segment 16. The pin is used inconjunction with pelleting tube 18, which has an upper tube opening 20,an opposing lower tube opening 22, and an inner surface. Tube 18 has aninner diameter sized to provide a sealing fit between the inner surfaceand the upper segment of the pin. The assembly further includes a funnel24 in the form of an inverted cone structure concentrically taperingfrom an upper rim 26 down to a narrow outlet 28 aligned with the uppertube opening 20. It will be appreciated that the a functionallyequivalent reservoir can be substituted for the funnel, providing thatthe reservoir is large enough to contain the intended volume of theselected pellet composition and has an outlet that enables downward flowof the pellet composition in a molten state. The funnel and tube aretherefore in fluid communication so that the flowable pelleting materialcan enter the tube from the funnel.

To manufacture a pellet, the pin tip 14 is inserted into tube 18 throughlower tube opening 22, and the pin is then moved upward through the tubetoward the funnel until the pin tip reaches the upper tube opening; thepin is shown positioned in this manner in FIG. 2A. At that point, theupper tube opening having been sealed with the upper segment of the pin,the pellet composition 30, containing a pharmacologically active agent,is placed into the funnel. The pellet composition may be placed into thefunnel in molten, i.e., flowable, form, or it can be heated within thefunnel until rendered flowable if a temperature control mechanism isoperably connected to the funnel body. The pin is then partiallywithdrawn from the tube through the lower tube opening, such that thepin tip is lowered a selected distance 32 from the upper tube opening,as illustrated in FIG. 2B. This draws the molten pellet composition 30down into the tube via a siphoning effect. After the pin tip has beenlowered, the pellet composition is allowed to cool so as to form thehardened pellet within the tube. The pin is then completely removed fromthe tube, and the pellet removed using any suitable means. The pellet soformed has a pellet length corresponding to the distance that the pintip is lowered, i.e., the “selected distance,” and a pellet diameterdefined by the inner diameter of the pelleting tube. In a preferredembodiment, the assembly includes a means for maintaining the pelletingtube in place, such as the collar 34 shown in FIGS. 2A and 2B.

To form a core-and-shell type of pellet, illustrated in FIGS. 3A through3E, a pellet manufacturing assembly 36 includes a pelleting tube 38 anda funnel 40 as described above for monolith manufacture. In this case,however, an elongated pin 42 is used that is composed of two axiallyaligned, substantially cylindrical segments of different diameters thatare longitudinally adjacent, with a wider lower segment 44 and anarrower upper segment 46 that terminates in the pin tip 48. Inaddition, the relative dimensions in this context are such that asealing fit is provided between the inner surface of the tube and thewider, lower segment of the elongated pin, while, as indicated in FIG.3A, the upper, narrower segment of the pin is significantly narrowerthan the inner diameter of the tube.

Formation of a core-and-shell pellet begins by inserting the pin tipinto the lower tube opening and moving the pin upward through the tube,toward the funnel, until the pin tip and then the upper pin segmentprotrude from the upper tube opening into the funnel; this configurationis shown in FIG. 3A. Upward, vertical movement of the pin through thetube in this way brings the lower pin segment into the tube, with theupper tube opening sealed as a result. As the shell is made first, theshell composition 50 is then placed into the funnel; see FIG. 3B. Aswith monolith manufacture, the shell composition may be heated untilrendered flowable prior to placement in the funnel, or it can be heatedwithin the funnel if a suitable heating apparatus is operably connected.To make the shell, the lower pin segment is gradually withdrawn from thetube through the lower tube opening, thus lowering the upper pin segmentinto the tube and simultaneously drawing the flowable shell compositioninto the concentric space forming between the upper, narrow segment ofthe pin and the inner surface of the tube as the pin is lowered; seeFIG. 3C. The hot shell composition is allowed to cool, thereby hardeninginto a shell 52 formed around the upper segment of the pin, within thetube, as shown in FIG. 3C.

The core composition 54 (see FIG. 3D) is added into to the funnel 40after cleaning, and is either in molten, flowable form prior toplacement in the funnel or heated therein, as described above. Thenarrower, upper pin segment 46 is then gradually lowered within thetube, drawing the core composition down into the shell; see FIG. 3E. Thecore-and-shell pellet so formed is allowed to cool, with the molten core56 fusing within the shell 52 during the cooling process, and harden toa degree sufficient to allow complete removal of the pin without anyflow of pelleting material. The finished pellet can then be removed fromthe tube using any suitable means.

The methodology allows facile control over pellet dimensions, insofar asthe diameter of the pellet formed is determined by the inner diameter ofthe tube, and the length of the pellet is determined by the extent towhich the pin or individual segments thereof are lowered within thetube, before the pellet, core, or shell is allowed to cool and harden.It will therefore be appreciated that the method can be readily adaptedto make pellets of different dimensions. That is, pellets of differentdiameters can be made by using a narrower or wider tube, and,correspondingly, different core diameters, while pellet length can beadjusted by lowering the pin within the tube to a lesser or greaterdegree as molten pellet material is drawn into the tube interior.

The above-described process for making core-and-shell pellets can beadapted to make pellets with more than one shell, by using an elongatedpin with multiple segments and segment-by-segment step-wise lowering ofthe pin within the tube, as each shell is made and allowed to hardenwithin the pelleting tube.

Channel capping, as explained earlier in this section, facilitatespellet formation in a manner that allows the interior pellet to fuse andcontract without formation of internal cavities or sinks. This is done,in part, by lowering the pin within the tube in a gradual manner, and inpart by allowing a small amount of pelleting composition to remain inthe funnel just above the funnel-tube junction.

In a preferred approach, channel capping is carried out in shellformation, core formation, or, more preferably, both. Followingcompletion of pellet manufacture, the completed pellet is released usingany effective method.

It should be noted that the invention is not limited with respect to theaforementioned methods of manufacture, and that other methods for makingthe pellet implants are possible, including modified versions of theaforementioned methods or entirely different methods known to those ofordinary skill in the art.

To scale up pellet manufacture, it will be appreciated that automationof one or more aspects of the method is desirable. For example, anautomated pin positioning means would be useful for moving the elongatedpin vertically into and through the pelleting tube and then withdrawingthe pin, wherein the pin would be withdrawn stepwise in a core-and-shellmanufacturing method such as that described above. As another example,an automated means for filling the funnel or a functionally equivalentreservoir with pelleting material, including shell material and corematerial, would be desirable, as would a reservoir cleaning techniqueand a pellet removal system. Other such automated means will be apparentto those of ordinary skill in the art and/or are described in thepertinent texts and literature.

It is to be understood that while the invention has been described inconjunction with a number of specific embodiments, the foregoingdescription as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications will be apparent to those skilled in theart. All patents, patent applications, and publications mentioned hereare hereby incorporated by reference in their entireties.

EXPERIMENTAL

General Procedure A—Monolithic Pellet Manufacture:

Subdermally implantable monolithic pellets of the invention wereprepared in these examples using a hot melt method, as described below.

System preparation: A funnel as illustrated in the hot melt moldingsystem of FIG. 2A and 2B was heated to a temperature just high enough torender the pellet composition flowable. A length of PTFE tubing, cut toallow a seal to form between the heated funnel and the tubing, wasplaced into a heated collar to bring the temperature to just below thetransition temperature of the powder, i.e., the temperature at which thepowder transforms from a substantially solid form into a flowable form.The collar, with PTFE tube attached, was placed on a drawing pin suchthat the pin extended through the length of the tube, terminating justbelow the funnel. The pin is sized such that its diameter issufficiently close to the inner diameter of the PTFE tube to provide asealing fit therebetween. The funnel was then brought into contact withthe top of the heated collar and therefore with the pin as well, suchthat the channel's opening was aligned with the center of the pin,collar and tube. This arrangement created a seal between the channel'sopening and the upper region of the PTFE tubing.

Materials: cholesterol; phosphatidylcholine or lecithin; andetonogestrel.

Monolithic pellet preparation: All materials were fully dissolved inethanol, and the ethanol was then evaporated to leave a homogeneouscomposition of the pellet components as a powder. These materials may,alternatively, be slurried by hand or machine mixing in any USP gradeorganic solvent, with ethanol preferred. In formulations withfree-flowing dry powders, dry-mixing equipment, such as V-blenders orother type of blenders, may be used.

The powdery pellet composition was poured directly into the heatedfunnel. The amount of material added to the funnel was calculated toprovide enough material to fill the PTFE tubing cavity as well as createa residual in the funnel that capped off the PTFE tubing, therebycausing a complete fill of the cavity and preventing air from enteringand creating voids and cracks in the pellet. As the powdered materialreached its transition temperature and became flowable, the pin waslowered through the PTFE tubing, drawing the pellet composition into thetube and forming an elongated rod.

Pellet post processing: The rod was allowed to cool in ambientconditions in place for approximately 30 to 60 seconds prior to removingthe collar and PTFE tube for cooling at room temperature. Once the rodcooled, it was ejected from the PTFE tube with a pin and inspected. Itwas then available for trimming to predetermined pellet dimensions usinga hot knife.

General Procedure B—Manufacture of Core-and-Shell Pellets,Drug-Containing Core (“Core-Type Pellets”):

Modifications were made to the above procedure for making monolithicpellets in order to make core-and-shell pellets, i.e., subdermallyimplantable pellets with a drug-containing core in an inert shell. Thepellet manufacturing assembly used to make core-and-shell pellets isschematically illustrated in FIGS. 3A through 3E.

System preparation: The hot melt molding system was set up and readiedfor pellet manufacture as described above with respect to monolithicpellets.

Materials for the drug-containing core: cholesterol; phosphatidylcholineand/or lecithin; and etonogestrel.

Materials for the inert shell: lipid only, e.g., cholesterol and/orphosphatidylcholine.

Preparation: All core materials were fully dissolved in ethanol, and theethanol was then evaporated to leave a homogeneous composition of thecore components as a powder. Shell materials were slurried in ethanol,and the ethanol was then evaporated to leave a homogeneous compositionof the shell components as a powder.

In this case, in contrast to monolith manufacture, as described inGeneral Procedure A, a double pin was used to fabricate thecore-and-shell pellet in two stages. The double pin was made byassembling a narrower pin on top of and in axial alignment with thesomewhat wider pin used for monolith preparation, the narrower pinforming an extended narrower segment of an integral pin structurecomprised of two segments of different diameter.

The powdery shell composition was poured directly into the heatedfunnel. The amount of material added to the funnel was calculated toprovide enough material to fill the PTFE tubing cavity, with thenarrower pin segment container therein, and create a residual in thefunnel that capped off the PTFE tubing. This resulted in completefilling the cavity and preventing air from entering and creating voidsand cracks in the shell. As the powdered material in the heated funnelbegan to coalesce and flow, the pin was lowered through the PTFE tubing,drawing the flowable shell material, along with the extended narrowersegment of the pin, into the tube and forming an elongated cylinderaround the narrower pin segment. The cylinder thus formed was composedof the shell composition and serves as the shell of the final pellet. Toform the core, the funnel was wiped clean of shell material and themixed core powder was then added into the funnel. After heating the corecomposition until flowable, the pin was drawn down a second time, sothat the narrower upper segment was withdrawn almost completely from thesolidified shell. The tight contact between the shell and pin, andbetween the tube and funnel, resulted in a partial vacuum as the pin iswithdrawn from the shell, thereby siphoning flowable core material fromthe funnel into the shell. The core was allowed to cool and hardenwithin the shell. The tube was then removed from the apparatus and thecore-and-shell pellet allowed to further cool at room temperature beforebeing extracted from the tube.

General Procedure C—Manufacture of Core-and-Shell Pellets,Drug-Containing Shell (“Shell-Type Pellets”):

Core-and-shell pellets with a drug-containing shell and an inert core(i.e., “shell-type pellets) were manufactured using the process ofGeneral Procedure B, except that the drug-containing material was addedto the funnel first to form the shell, and the inert material addedsecond to form the core.

Unless otherwise indicated, all percentages herein are weight % (wt. %),all ratios are weight ratios, and all width and length measurements arein millimeters.

Example 1 Monolithic Pellets: Effect of Pellet Diameter on Release Rateand Duration

Rod-shaped, substantially cylindrical monolithic pellets, havingidentical compositions but differing in diameter, were made usingGeneral Procedure A.

Composition: 85 wt. % etonogestrel (“ENG”), 3 wt. % phosphatidylcholine(“PC”), and 12 wt. % cholesterol (“CH”).

The pellets made were both 4 mm in length, with one pellet having adiameter of 1.7 mm (a “monolithic thin” type of pellet) and the otherpellet having a diameter of 2.8 mm (a “monolithic thick” type ofpellet). Drug release rate in 95.0% denatured ethanol (i.e., anhydrousethanol denatured with 5 vol. % methanol and 5 vol. % isopropanol) and5% deionized water was evaluated over a time period of about 30 minutes,as follows:

50.0 ml of the 95.0% ethanol dissolution medium were added to a 125 mLErlenmeyer flask, which was then sealed with paraffin film. Twocapillary tubes were inserted through the film and into the dissolutionmedium, and were connected to a peristaltic pump that circulated thesolution at 4 mL/min through a 0.2 mm path length quartz cuvette in aUV-Vis spectrometer. The pellet was dropped into the dissolution medium,which was stirred at room temperature in the flask on an orbital shakerset to 150 rpm. The absorbance was measured at 240 nm, as ENG absorbsstrongly at that wavelength while the excipients, CH and PC, do not.Absorbance measurements were taken at 1-second intervals for 15 to 180minutes until the spectrometer response remained constant, indicatingcomplete dissolution of the pellet.

The dissolution profiles are shown in FIG. 4. The thinner monolithicpellets clearly stopped ENG release much earlier than thicker, moretraditional pellets, and they also started with a lower dose. As may beseen in the figure, increasing the pellet diameter increased bothduration of drug release, i.e., the time period during which ameasurable drug concentration was seen, and the drug release rate.

Example 2 Monolithic Pellets: Effect of Pellet Length on Release Rateand Release Duration

Two groups of rod-shaped, substantially cylindrical monolithic pellets,having identical compositions but differing in length, were made usingGeneral Procedure A.

Composition: 85 wt. % ENG, 3 wt. % PC, and 12 wt. % CH.

The pellets made were both 2.8 mm in diameter, with one pellet having alength of 4 mm and another pellet having a length of 6 mm. Thedissolution profiles obtained using the methodology described in Example1 are shown in FIG. 5. As may be seen in the figure, the two pelletsreleased drug over a time period of similar duration, but the shorterpellets gave rise to a shallower slope for the decreasing rate ofetonogestrel release, meaning that the release rate for the longerpellets decreased faster than that of the shorter pellets.

Example 3 Core-Type Pellets: Release Rate and Duration

General Procedure B was followed to prepare pellets having a core of 85wt. % ENG, 12 wt. % CH, and 3 wt. % PC, and a shell of 97 wt. % CH and 3wt. % PC. The diameter of each core was 1.6 mm and each shell was 0.6 mmthick, giving a total pellet diameter of 2.8 mm. Pellet length was 4 mm.Drug release over time was evaluated in 95% ethanol as described inExample 1. Results are shown in the dissolution profile of FIG. 6 (seethe curve corresponding to the pellet length of 4 mm).

Example 4 Core-Type Pellets: Effect of Pellet Length on Release Rate andDuration

General Procedure B was followed to prepare core-type pellets having acore of 85 wt. % ENG, 12 wt. % CH, and 3 wt. % PC, and a shell of CH andPC in a 97:3 weight ratio. For purposes of evaluating the effect ofpellet length on release rate and duration with core-type pellets, acore pellet was prepared as in Example 3, but with a pellet length of 2mm. Drug release rate was evaluated as described in Example 1, and thedissolution profiles are shown in FIG. 6. Comparing the figure with therelease profiles of the monolithic pellets shows that the ENG releaserate is significantly slower with core-type pellets than with monolithicpellets. Doubling the core pellet length from 2 mm to 4 mm doubled theENG release duration while maintaining a fairly even ENG release rate ofapproximately 5 mg/hr.

Example 5 Shell-Type Pellets: Effect of Pellet Length on Release Rateand Duration

General Procedure C was followed to prepare shell-type pellets having acore of CH and PC in a 97:3 weight ratio and a shell of 85 wt. % ENG, 12wt. % CH, and 3 wt. % PC. The diameter of each core was 1.6 mm and eachshell was 0.6 mm thick. As in the preceding example, a first pellet wasprepared that was 2 mm in length, and a second pellet was prepared thatwas 4 mm in length. Drug release rate in ethanol was evaluated asdescribed in Example 1. The dissolution profiles for the two pelletgroups are shown in FIG. 7. In this case, increasing the length of thepellet did not substantially change the duration of ENG release, but didincrease ENG release rate. Shell pellets are designed to have a rapidcessation of ENG release once the shell has eroded to the CH core. Thiscan be seen with the 4 mm shell pellet, compared to the 4 mm monolithicpellet, but was not clearly seen in the 2 mm shell pellet.

For purposes of comparison, the dissolution profiles obtained for thethick monolithic pellets and thin monolithic pellets (Example 1) areshown as a group in FIG. 8, with the dissolution profiles obtained forcore-type pellets (Example 3) and shell-type pellets (Example 5), allpellets 4 mm in length. In FIG. 8, Profile A corresponds to themonolithic thick and thin pellets, Profile B corresponds to thecore-type pellets, and Profile C corresponds to the shell-type pellets.

Example 6 Effect of Drug Concentration on Drug Release Profile

In order to assess the concentration of drug in the implant on the drugrelease profile, four types of pellets were made, with two drugconcentration subgroups prepared for each of the four pellet types:

Type (I), Monolithic thick pellets. Dimensions: Diameter, 2.8 mm,length, 6 mm. Type (I), subgroup (A): 85% ENG, 12% CH, 3% PC. Type (I),subgroup (B): 20% ENG, 77% CH, 3% PC.

Type (II), Monolithic thin pellets. Dimensions: Diameter, 1.7 mm;length, 4 mm.-Type (II), subgroup (A): 85% ENG, 12% CH, 3% PC. Type(II), subgroup (B): 20% ENG, 77% CH, 3% PC.

Type (III), Core-type pellets. Dimensions: Core diameter, 1.6 mm; shellthickness, 0.6 mm; length, 4 mm. Type (III), subgroup (A): 85% ENG, 12%CH, 3% PC core and 97% CH, 3% PC shell. Type (III), subgroup (B): 20%ENG, 77% CH, 3% PC core and 97% CH, 3% PC shell.

Type (IV), Shell-type pellets. Dimensions: Core diameter, 1.6 mm; shellthickness, 0.6 mm; length, 4 mm. Type (IV), subgroup (A): 85% ENG, 12%CH, 3% PC shell and 97% CH, 3% PC core. Type (IV), subgroup (B): 20%ENG, 77% CH, 3% PC shell and 97% CH, 3% PC core.

The release rate results obtained using the method of Example 1 can beseen in the comparative release profiles of FIGS. 9 through 12. With allfour pellet types, thick, thin, core and shell, the rate of ENG releaseincreased with an increase in ENG content, while the release durationdecreased with an increase in ENG content. While the approximatelyfour-fold greater ENG content in the 85% ENG pellets relative to the 20%ENG pellets might have been expected to give an approximately four-foldgreater release rate of ENG, the EN release from the 85% pellets was,surprisingly, substantially higher than four-fold faster. ENG releasefrom pellets with higher CH content is slowed because the aqueoussolubility of a 20% ENG/80% CH solid mixture is lower than onecontaining 85% ENG/15% CH.

Example 7 Effect of Changing Excipient on Drug Release Profile

In order to assess the impact of a change in excipient on drug releaseprofile from pellet implants, several monolithic pellets were made withdifferent excipient compositions but were otherwise identical. Pelletdimensions: diameter 2.8 mm, length 6 mm. Composition: 85% ENG, 15%excipient. Pellets were made with the excipients indicated below.

Excipient 1: CH/PC at a 4:1 weight ratio.

Excipient 2: Propylene glycol (PG).

Excipient 3: Polyethylene glycol 8000 (PEG-8000).

Excipient 4: Polyethylene glycol 300 (PEG-300).

Excipient 5: Palmitic acid (PA).

Dissolution profiles obtained using the method of Example 1 are providedin FIGS. 13 through 17 for Excipients 1 through 5, respectively.

At 85% ENG, this major component, i.e., the active agent, controlled theoverall release profile when relatively small molecules were used as theexcipient. The addition of a large polymeric molecule, PEG-8000, wasfound to inhibit ENG release and increase the release duration.

Example 8 In Vivo Evaluation

Five types of pellets were prepared using the procedures of the earlierexamples:

ENG thick monolithic (85% ENG, 12% CH, and 3% PC; diameter 2.8 mm,length 6 mm;

ENG thin monolithic (85% ENG, 12% CH, and 3% PC; diameter 1.7 mm, length4 mm;

ENG shell (core of CH/PG at a 97:3 ratio; shell of 85% ENG, 12% CH, and3% PG; core diameter 1.6 mm, shell thickness 0.6 mm, and length 4 mm;

ENG core (core of 85% ENG, 12% CH, and 3% PG; shell of CH/PC at a 97:3weight ratio; core diameter 1.6 mm, shell thickness 0.6 mm, and length 4mm;

NET (norethindrone) thick monolithic (85% NET, 15% CH); diameter 2.8 mm,length 6 mm.

The five pellet types were implanted subcutaneously into eight rats perpellet type (except for NET thick monolithic, where pellet one waspulled out by the animal sometime during day 1). The number of pelletsimplanted per rat was chosen to keep the total ENG doses similar (32±5mg). Pellets were implanted separately on the animal's back. Ratsreceived a 1× ENG or NET thick monolithic pellet above one front leg, or2× shell pellets above both front legs, or 4× thin monolithic pellets orcore pellets above all four legs. Blood plasma levels were evaluated atday 1, day 4, day 14, day 30, and day 90. Extended release was achievedwith all pellets, as indicated by FIG. 18.

Then, the unreleased progestin per rat was averaged for each pellettype, and the amount released was calculated by difference from theaverage starting content based on the analysis of pellets made in thesame batches as those implanted. FIG. 19 shows that the amount ofprogestin initially released from the pellets tightly correlates withthe exposed surface area, supporting the same surface erosion mechanismin vivo as that seen in vitro, and also supporting a correlation betweenENG loss and blood levels, implying that the amount of drug released andthe rate of drug release can be controlled by varying exposed ENGsurface area. A good correlation showing a linear dose response wasfound between the blood concentration integrated over the three-monthexposure (i.e., the area under the curve or “AUC”) and the amount ofprogestin released from the pellets, as seen in FIG. 20.

Example 9 Naproxen Monoliths and Core-Type Pellets

Monolithic and core-type pellets of the invention were made with theactive agent naproxen ((S)-(+)-2-(6-methoxy-2-naphthyl)propionic acid)),a non-steroidal anti-inflammatory agent with a melting point of 153° C.(obtained from VWR, in the form of the free acid). Monolithic pelletswere prepared as described in General Procedure A, containing 85 wt. %naproxen, 12 wt. % cholesterol, and 3 wt. % phosphatidylcholine.Core-type pellets were prepared as described in General Procedure B,with a shell of 97 wt. % cholesterol and 3 wt. % phosphatidylcholine,and a core composition of 100% naproxen fed into the shell during pelletmanufacture. Monoliths and core-type pellets were 2.8 mm in diameter,with monoliths 5.5 mm in length and core-type pellets 4 mm in length.Naproxen release from both pellet types was evaluated; results are shownin FIG. 21. As FIG. 21 indicates, the naproxen core pellet providedapproximately zero-order (i.e., steady-state) release, while thenaproxen monolith gave a release profile in which release rate decreasedapproximately linearly until the drug was depleted.

Example 10 Methocarbamol Monoliths and Core-Type Pellets

Monolithic and core-type pellets of the invention were made with theactive methocarbamol, an antispasmodic agent with a melting point of 93°C. (obtained from VWR). As in Example 9, monolithic pellets wereprepared as described in General Procedure A, containing 85 wt. %methocarbamol, 12 wt. % cholesterol, and 3 wt. % phosphatidylcholine.Core-type pellets were prepared as described in General Procedure B,with a shell of 97 wt. % cholesterol and 3 wt. % phosphatidylcholine,and a core composition of 100% methocarbamol fed into the shell duringpellet manufacture. As in Example 9, monoliths and core-type pelletswere 2.8 mm in diameter, with monoliths 5.5 mm in length and core-typepellets 4 mm in length. Methocarbamol release from both pellet types wasevaluated; results are shown in FIG. 22. As with the naproxen monolithsand core-type pellets in the preceding example, FIG. 22 indicates thatthe methocarbamol core pellet provided approximately zero-order release,while the methocarbamol monolith gave a release profile in which releaserate decreased approximately linearly until the drug was depleted.

Examples 11 and 12 Cholecalciferol and Acetaminophen Pellets

The procedures of Examples 9 and 10 were repeated to prepare analogousmonolithic and core-type pellets with cholecalciferol (Vitamin D₃,melting point 84.5° C.) (Example 11) and acetaminophen (melting point168° C.) (Example 12), both active agents obtained from VWR. Drugrelease was evaluated in Examples 9 and 10, with results shown in FIG.23, for cholecalciferol, and FIG. 24, for acetaminophen.

In FIG. 25, the release profiles are plotted for each of the corepellets prepared in Examples 9-12, i.e., for naproxen, methocarbamol,cholecalciferol, and acetaminophen, while FIG. 26 shows the releaseprofiles for the corresponding monolithic pellets.

Active agent release rates and release profiles with the present drugdelivery systems depend on several factors including water solubility,crystallinity melting point (i.e., stability of crystalline form), andactive agent-excipient interactions that may alter solubility and/orcrystalline stability. The results in Examples 9-12 indicate that, as ageneral trend, faster release from the monolithic pellets correlateswith faster release from the core pellet with the same active agent.However, the correlation is not absolute, presumably because each activeagent interacts differently with the excipient composition in themonolithic pellets that is not present in the core material.

It should also be noted that active agent release from monolithicpellets is relatively high at the beginning and tapers off, while activeagent release from the core-type pellets is relatively stable over theduration of drug release. Either type of pellet may be preferred,depending on the particular active agent.

We claim:
 1. A method for making a core-and-shell type of pellet forcontrolled release of a pharmacologically active agent, the methodcomprising: (a) providing (i) an elongated pin comprising two axiallyaligned, substantially cylindrical adjacent segments of differentdiameters, with a wider lower segment and a narrower upper segment thatterminates in a pin tip, (ii) a pelleting tube having an upper tubeopening, an opposing lower tube opening, an inner surface, and an innerdiameter sized to provide a sealing fit between the inner surface andthe lower segment of the pin, and (iii) a funnel having an outletaligned with the upper tube opening; (b) inserting the pin tip into thelower tube opening and moving the pin upward through the tube toward thefunnel until the pin tip and upper pin segment protrude from the uppertube opening into the funnel, thereby bringing the lower segment withinthe tube; (c) placing a molten shell composition in the funnel; (d)gradually withdrawing the lower segment from the tube, thereby loweringthe upper segment into the tube and simultaneously drawing the shellcomposition into a concentric space between the upper segment and theinner surface of the tube; (e) allowing the shell composition to cooland thereby harden into a shell formed around the upper segment withinthe concentric space; (f) placing a molten core composition into thefunnel; and (g) gradually lowering the upper segment within the tube,thereby drawing the core composition into the shell to form a core,wherein the shell composition and/or core composition contain apharmacologically active agent.
 2. The method of claim 1, wherein thepharmacologically active agent is in the shell composition and not inthe core composition.
 3. The method of claim 1, wherein thepharmacologically active agent is in the core composition and not in theshell composition.
 4. The method of claim 1, wherein at least about 80wt. % of the pharmacologically active agent in the pellet is in thecore.
 5. The method of claim 1, wherein at least about 80 wt. % of thepharmacologically active agent in the pellet is in the shell.
 6. Themethod of claim 1, wherein the core and the shell each contain at leastabout 20 wt. % of the pharmacologically active agent in the pellet. 7.The method of claim 1, wherein the core contains a firstpharmacologically active agent and the shell contains a secondpharmacologically active agent.
 8. The method of claim 1, wherein thepharmacologically active agent has an aqueous solubility of less thanabout 50 mg/mL.
 9. The method of claim 1, wherein the active agentcomprises an analgesic agent; an anti-anxiety agent; an anti-arthriticagent; an anti-asthmatic agent; an anticancer agent; an anticholinergicagent; an anticholinesterase; an anticonvulsant; an antidepressant; anantidiabetic agent; an antidiarrheal agent; an anti-emetic agent; anantihistamine; an antihyperlipidemic agent; an anti-infective agent; ananti-inflammatory agent; an antimigraine agent; an anti-obesity agent;an antipruritic agent; an antipsychotic agent; an antispasmodic agent;an agent for treating a neurodegenerative disease; a cardiovascularmedicament; a diuretic agent; a gastrointestinal medication; a hormone;an anti-hormone; a hypnotic agent; an immunosuppressive agent; aleukotriene inhibitor; a narcotic agonist or antagonist; aneurotransmitter; nicotine; a nucleic acid; a peptide drug; a nutrient;a sympathomimetic agent; a thrombolytic agent; a vasodilator; or acombination thereof.
 10. The method of claim 9, wherein thepharmacologically active agent comprises an antipsychotic agent.
 11. Themethod of claim 9, wherein the pharmacologically active agent comprisesan anti-inflammatory agent.
 12. The method of claim 11, wherein theanti-inflammatory agent is a nonsteroidal anti-inflammatory agent. 13.The method of claim 9, wherein the pharmacologically active agentcomprises a gastrointestinal medication.
 14. The method of claim 13,wherein the gastrointestinal medication is a proton pump inhibitor. 15.The method of claim 9, wherein the active agent comprises an anticanceragent.
 16. The method of claim 15, wherein the anticancer agent isselected from an anti-metabolite, an anti-microtubule agent, a cytotoxicantibiotic, a topoisomerase inhibitor, an aromatase inhibitor, a GnRHanalogue, a hormone receptor antagonist, a hormonal agent, ananti-angiogenic agent, an anti-metastatic agent, and a combinationthereof.
 17. The method of claim 9, wherein the active agent comprisesan anti-infective agent.
 18. The method of claim 17, wherein theanti-infective agent is selected from an antibiotic, an antiviral agent,an antifungal agent, an antiparasitic agent, and a combination thereof.19. The method of claim 9, wherein the active agent comprises acardiovascular medicament.
 20. The method of claim 9, wherein thecardiovascular medicament is selected from an antiarrhythmic agent, anantihypertensive agent, an anti-anginal agent, and a combinationthereof.
 21. The method of claim 9, wherein the active agent comprisesan anti-convulsant agent.
 22. The method of claim 9, wherein the activeagent comprises an agent for treating a neurodegenerative disorder. 23.The method of claim 9, wherein the active agent comprises a hormone. 24.The method of claim 23, wherein the hormone comprises a steroid.
 25. Themethod of claim 9, wherein the active agent comprises a nutrient. 26.The method of claim 25, wherein the nutrient comprises a vitamin. 27.The method of claim 1, wherein the shell, the core, or both the shelland core comprise an excipient composition.
 28. The method of claim 27,wherein the excipient composition is lipophilic.
 29. The method of claim28, wherein the excipient composition comprises a sterol ester.